RU2519748C2 - Method (versions) and preparation for modification of eating behaviour - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions relates to medicine and can be used for modification of eating behaviour in a subject. For this purpose peripheral introduction of PYY in an amount, efficient for achieving physiological levels of PYY_3-36 in blood, plasma and serum, determined after food intake, is performed; or performed is peripheral introduction of PYY agonist in an amount, efficient for imitation of physiological levels of PYY_3-36 in blood, plasma or serum, determined after food intake with modification of eating behaviour, by reducing intake of calories, food consumption or appetite reduction or increase of energy consumption in the subject. Also claimed is application of PYY or its agonist as an active ingredient in production of medication.

EFFECT: group of inventions provides weight reduction in the subject due to reduction of intake of calories, appetite reduction or increase of energy consumption in the subject.

50 cl, 9 dwg, 6 ex

Description

FIELD OF THE INVENTION

This invention relates to methods of modifying eating behavior and the use of agents for controlling appetite, nutrition, food intake, energy expenditure and calorie intake, especially in case of obesity.

Relevant studies have been carried out with support from the United States Government under grants from the National Institute of Health RR00163, DK51730, and DK55819. The United States Government has certain rights in this invention.

State of the art

According to the National Health and Nutrition Examination Survey (NHANES III, 1988-1994), one third to half of men and women in the United States are overweight. In the United States, sixty percent of men and fifty-one percent of women age 20 and over are either overweight or obese. In addition, in the United States, a large percentage of children are overweight or obese.

The cause of obesity is complex and multifactorial. There is a growing body of evidence that suggests that obesity is not just a problem of self-control, but a complex disorder that includes appetite regulation and energy metabolism. In addition, obesity is associated with many conditions associated with increased morbidity and mortality. Although the etiology of obesity has not been fully established, it is believed that genetic, metabolic, biochemical, cultural and psychological factors are involved. Obesity has generally been described as a condition in which excess body fat is a risk factor for a subject's health.

There is strong evidence that obesity is associated with increased morbidity and mortality. The risk of developing a disease, such as the risk of developing cardiovascular disease and the risk of developing type 2 diabetes, increases independently with an increase in body mass index (BM1). In fact, this risk is quantified as a five percent increase in the risk of developing heart disease in women and a seven percent increase in the risk of developing heart disease in men for each BM1 point exceeding 24.9 (see articles by Kenchaiah et al., N. Engl . J. Med. 347: 305, (2002); Massie, N. Engl. J. Med. 347: 358, (2002)). In addition, there is sufficient evidence that weight loss in obese subjects reduces the risk factors for serious diseases. Even a slight decrease in body weight, such as 10% of the initial body weight in adult subjects, both overweight and obese, was associated with a decrease in risk factors, such as hypertension, hyperlipidemia and hyperglycemia.

Although diet and exercise are a simple way to reduce weight gain, overweight and obese subjects often cannot sufficiently control these factors to effectively lose body weight. There is the possibility of pharmacotherapy. The Food and Drug Administration has approved a number of drugs for weight loss that can be used as part of a comprehensive weight loss program. However, many of these drugs have serious harmful side effects. If the use of less invasive methods is ineffective and there is a high risk for the patient to develop obesity-related diseases or death, surgical intervention aimed at reducing body weight is the option for carefully selected patients with clinically severe obesity. However, these methods of treatment are in the high-risk area and are suitable for use only on a limited number of patients. Not only obese subjects desire weight loss. People with body mass located within the recommended limits, for example, in the upper region of the recommended interval, may have a desire to reduce their body weight in order to bring it closer to the ideal body weight. Thus, there remains a need for agents that can be used to affect body weight in subjects who are overweight or obese.

Disclosure of invention

In this context, evidence is presented that the peripheral administration of PYY or an agonist to a subject results in reduced food absorption, calorie intake and appetite, as well as a change in energy metabolism. A subject can be represented by any subject, including, but not limited to, a person. In a number of embodiments, a subject desiring to lose body weight is obese, overweight, or suffering from a body weight disorder. Administration to the subject of PYY _3-36 may be preferred.

In one embodiment, a method for reducing calorie intake in a subject is described. The method includes peripherally administering to the subject a therapeutically effective amount of PYY or an agonist thereof, thereby reducing calorie consumption by the subject.

In another embodiment, a method for reducing appetite in a subject is described. The method includes the peripheral administration of a therapeutically effective amount of PYY or an agonist thereof to a subject, thereby reducing appetite in the subject.

In a further embodiment, a method for reducing food intake in a subject is described. The method includes the peripheral administration of a therapeutically effective amount of PYY or an agonist thereof to a subject, thereby reducing food intake in the subject.

In yet another embodiment, a method for increasing the energy expenditure of a subject is described in this context. The method includes the peripheral administration of a therapeutically effective amount of PYY or an agonist thereof to a subject to thereby increase the energy expenditure of the subject.

Also described is a method of reducing calorie intake, food intake or appetite in a human subject. The method includes peripherally injecting a subject with a therapeutically effective amount of PYY or an agonist thereof in a pharmaceutically acceptable carrier in a pulse dose to thereby reduce calorie intake, food intake or appetite in the subject.

In this context, information is presented that the peripheral administration of a PYY antagonist to a subject results in an increase in food absorption, calorie intake and appetite, as well as a change in energy metabolism. A subject can be any subject, including, but not limited to, a person. In some embodiments, the subject wishes to increase body weight or suffers from anorexia or cachexia.

The above and other features and advantages will be more apparent from the following detailed description of certain embodiments, which is preceded by a reference to the accompanying figures.

Brief Description of the Drawings

The Figure 1 presents a set of diagrams and digital images demonstrating the production of transgenic mice expressing EGFP (green fluorescence protein) in POMC (proopiomelanocortin) ARC neurons (arched nucleus). Figure 1 is a schematic diagram of the structure of the POMC-EGFP transgene. Figure 1a is a digital image showing the identification of one POMC neuron (arrow) using EGFP fluorescence (top) and IR-DIC microscopy (bottom) in a live ARC slice before recording electrophysiological data. Figure 1c presents a set of digital images demonstrating the colocalization (light, right) of EGFP immunoreactivity (left) and β-endorphin (middle) in POMC neurons of an arcuate nucleus. Columns showing the image scale: b and c, 50 microns. Figure 1d presents a set of diagrams showing the distribution of EGFP-positive soma neurons in the ARC nucleus. O = 5 cells, • = 10 cells.

Figure 2 shows a recording of a recording instrument and graphs demonstrating that activation of MOP-Rs leads to hyperpolarization of POMC neurons labeled with EGFP by opening G-protein-bound potassium channels of internal regulation. Figure 2a shows a recording of a recording device, which shows that met-enkephalin leads to hyperpolarization of POMC neurons and inhibits all action potentials. The horizontal bar shows the time at which 30 mM Met-Enk is applied to the slice by immersion. Figure 2b is a graph showing the current shift of met-enkephalin and the reversal potential under the influence of an extracellular K ⁺ concentration. Figure 2c is a graph showing that met-enkephalin activates MOP-R on POMC neurons. A Met-Enk current (30 μM) was observed and exposed to a MOP-R-specific STAP antagonist (1 μM) for 1 minute. Further exposure to STAR Met-Enk does not cause current. The figure represents data from three experiments.

Figure 3 shows recording instruments and graphs showing that leptin depolarizes POMC neurons through a non-specific cationic channel and reduces the GABAergic signal on POMC cells. Figure 3a shows recordings of recording instruments demonstrating that leptin depolarizes POMC neurons and increases the frequency of action potentials in the range from 1 to 10 minutes after administration. The figure is a representative example of entries made on 77 POMC neurons. Figure 3b is a graph showing that leptin causes concentration-dependent depolarization of POMC cells. Leptin-induced depolarization is defined as 0.1, 1, 10, 50, and 100 nM (EC50 = 5.9 nM) in (8, 7, 9, 3, 45) cells, respectively. Figure 3c is a graph showing that leptin depolarizes POMC cells by activating a non-specific cationic current. The figure represents a reaction in 10 cells. Figure 3d is a graph showing that leptin reduces the frequency of IPSCS in POMC cells. The figure shows as an example 5 cells in which leptin (at a concentration of 100 nM) reduces the frequency of IPSCS. Figure 3e shows recording instrument recordings demonstrating that leptin does not act on 5 adjacent non-fluorescent ARC neurons. Figure 3f shows the recordings of registration instruments showing that leptin causes hyperpolarization of 5 non-fluorescent ARC neurons.

Figure 4 presents a set of images showing that GABAergic inputs into POMC cells originate from NPY neurons that coexpress GABA. Figure 4a is a graph showing that NPY increases the frequency of miniIPSCS in POMC neurons. Figure 4b is a graph showing that D-Trp ⁸ -yMSH (7 nM), at a dose that selectively activates MC3-R, increases the frequency of GABAergic IPSCS in POMC neurons. Figure 4c shows records of registration instruments showing D-Trp ⁸ -yMSH causes hyperpolarization of POMC neurons. Figures 4a, 4b and 4c are representative. Figure 4d presents a set of digital images demonstrating the expression of NPY in the nerve endings adjacent to the POMC neurons in ARC. Nerve endings NPY (black, indicated by arrows); SOM neurons POMC (shown in gray). The scale bar is 10 microns in size. Figure 4e is a digital image showing the expression of GABA and NPY in nerve endings with synapses on neurons in ARC. GABA immunoreactivity (10 nm gold particles, arrows without tail) and NPY immunoreactivity (25 nm gold particles, arrows with tail) are found in separate populations of vesicles that are colocalized in synaptic buds that provide direct contact with the POMC neuron soma (DAB when contrasting with uranyl acetate and lead citrate, diffuse black cytoplasm staining). Column indicating scale, 1 μm. Figure 4f is a diagram of the NPY / GABA model and POMC neurons in ARC.

Figure 5 presents a set of graphs relating to the nutritional response of rats to PYY3-36. Figure 5a is a graph in the form of bars in the dark phase, summarizing the data on the absorption of food after intraperitoneal injection of PYY3-36. Rats with free access to food were injected with PYY _3-36 at the indicated doses (μg / 100 g) or physiological saline immediately before turning off the light and cumulative absorption of food was measured over 4 hours. The results are presented as mean ± sem (standard error) (n = 8 / group), * = p <0.05, ** = p <0.01, *** = <0.001 relative to saline. Figure 5b is a bar graph showing food intake after an intraperitoneal injection of PYY _3-36 . Fasted rats were injected with PYY _3-36 at the indicated doses (μg / 100 g) or saline and the cumulative absorption of food was measured over 4 hours. The results are presented as the mean value ± sem (n = 8 / group), * = p <0.05, ** = p <0.01, *** = <0.001 relative to saline. Figure 5c is a bar graph showing the cumulative absorption of food after an intraperitoneal injection of saline or PYY _3-36 . Starving rats were injected with either physiological saline (black bars) or PYY _3-36 at a dose of 5 μg / 100 g (white bars) and cumulative food absorption was measured at the indicated time points. Results are expressed as mean ± sem (n = 12 / group), ** = p <0.01 relative to saline. Figure 5d shows a linear graph of weight gain during the chronic treatment period of PYY _3-36 . Rats were injected intraperitoneally twice daily for 7 days with PYY _3-36 at a dose of 5 μg / 100 g (white squares) or saline (black inverted triangles). Weight gain was calculated daily. Results are expressed as mean ± sem (n = 12 / group), ** = p <0.01 relative to saline.

Figure 6 presents a set of digital images of c-fos expression in Pomc-EGFP mice. Figures 6a and 6b show digital images of representative sections (parietal region 1.4 mm ² ) reflecting the expression of c-fos in the arcuate nucleus of Pomc-EGFP mice as a response to intraperitoneal injection of saline (see Figure 6a) or PYY _{3- 36} (5 μg / 100 g) (see Figure 6b). A line showing an image scale of 100 microns. 3V - the third ventricle; ARC arcuate core. Figures 6c and 6d show digital images of representative sections showing POMC-EGFP neurons (see Figure 6c) and c-fos immunoreactivity (see Figure 6d) either in a colocalized form (light arrows) or separately from each other (one more dark arrow). The line showing the image scale, 25 microns.

The Figure 7 presents a set of graphs in the form of columns, reflecting the introduction of rats PYY _3-36 into the arcuate nucleus and the effects on nutrition of the intraperitoneal administration of PYY _3-36 to Y2r-null mice. Figure 7a shows a graph in the form of columns of food absorption after injection of PYY _3-36 into the arcuate core. Salted rats were injected with saline or PYY _3-36 into the arcuate nucleus at the indicated doses. 2 hours after injection, food absorption was measured, ** = p <0.01 relative to saline. Figures 7b and 7c are bar graphs depicting the nutritional response to PYY _3-36 in Y2r-null mice after intraperitoneal administration to the offspring of wild-type mice (see Figure 7b) and Y2r-null mice (see Figure 7c), starved for 24 hours, PYY _{3-36 was} injected at the indicated doses (μg / 100 g) or saline and cumulative absorption of food was measured over 4 hours. Results are presented as mean ± sem (n = 5 / group), * = p <0.05, ** = p <0.01 relative to saline.

The Figure 8 presents a set of images relating to the electrophysiological and neuropeptide response to PYY _3-36 and Y2A. Figure 8a shows a recording of a recording device demonstrating the effect of PYY _3-36 (concentration of 10 nM) on the frequency of action potentials in POMC neurons (recordings for the whole-cell configuration; n = 22) * p <0.05. PYY _3-36 is administered during D for 3 minutes; basic level line - 3 - 0 minutes; PYY _3-36 2-5 minutes and laundering 8-11 minutes. The insert shows a representative record of the membrane potential and the pulse rate of the action potential. Figure 8b is a graph showing the effect of PYY _3-36 (at a concentration of 10 nM) on the repetition rate of the action potential pulses in the potential clips of the patch clamp with free attachment to the cells (n = 8). The data characterizing individual cells were normalized with respect to the number of pulses over a period of 200 s before the addition of PYY _3-36 . Figure 8c shows a recording of a recording device and a graph of the effect of PYY _3-36 (at a concentration of 50 nM) on spontaneous IPSCS on POMC neurons (n = 13). The inset shows a representative IPSCS record before and after addition of PYY _3-36 (concentration of 50 nM), respectively. The results shown in Figures 8a-8c are expressed as the mean ± sem. Figures 8d and 8e show bar graphs showing the yield of NPY (see Figure 8d) and α-MSH (see Figure 8e) from hypothalamic explants in response to Y2A. Sections of the hypothalamus are incubated with artificial CSF (aCSF) with or without 50 nM Y2A for 45 minutes. Results are expressed as mean ± sem (n = 40), ** = p <0.01, *** = p <0.001 relative to saline.

The Figure 9 presents a set of graphs showing the effect of PYY _3-36 infusion on the appetite and absorption of food in humans. Figure 9a shows a graph of calorie intake from freely selected snacks 2 hours after infusion of saline or PYY _3-36 . Thin lines show individual changes in calorie intake for each subject with saline and PYY _3-36 . The thick line reflects the average change that occurs with two infusion options (n = 12). Figure 9b is a graph of a 24-hour calorie intake after infusion of saline or PYY _3-36 . Total calorie intake is shown for the 24-hour period after infusion of either saline or PYY _3-36 based on an estimate using a nutrition log. Data are given as mean ± sem (n = 12), [***] = p <0.0001 relative to saline. Figure 9c shows a graph of the appetite (relative scale). Analog visual metering systems (see Raben et al., Br. J. Nutr., 73: 517-30, (1995)) show a feeling of hunger during and after infusions. The results are presented as a deviation from the baseline level, and they are mean + sem values for all 12 subjects.

Sequence List

The nucleic acid and amino acid sequences listed in the attached list of sequences are given using standard letter abbreviations for nucleotide bases and a letter code for amino acids as defined in 37C.F.R. 1.822. Only one strand of each nucleic acid sequence is shown, but the inclusion of a complementary strand is implied by any reference to the presented strand.

The implementation of the invention

I. Abbreviations

α-MSH: α-melanocortin-stimulating hormone

ARC: arcuate core

EPSP: exciting postsynaptic potential

GABA: γ-aminobutyric acid

GFP, EGFP: Green Fluorescence Protein

IPSCS: inhibitory postsynaptic current

TPN: kilobase, (thousand base pairs)

kg: kilogram

MOP-R: mu-opioid receptor

mV: millivolt

NPY: neuropeptide Y

pmol: picomole

ROMS: proopiomelanocortin

RIA: radioimmunoassay

RPA: RNase Protection Assay

s.e.m: standard error

TN: tyrosine hydroxylase

μm: micromolar

V: volt

Y2A: N-Acetyl (Leu ²⁸ , Leu ³¹ ) NPY (24-36)

II. Terms

Unless otherwise specified, technical terms are used in accordance with their interpretation in this field. Definitions of terms common in molecular biology can be found in the monograph by Benjamin Lewin, Genes V (Genes V), published by Oxford University Press, (1994) (ISBN 0-19- [854287-9)]; in the monograph, ed. Kendrew et al. The Encyclopedia of Molecular Biology (The Encyclopedia of Molecular Biology), published by Blackwell Science Ltd., (1994) (ISBN 0-632-02182-9) and monograph ed. Robert A. Meyers, Comprehensive Desk Reference for Molecular Biology and Biotechnology (Molecular Biology and Biotechnology: a Comprehensive Desk Reference), published by VCH Publishers, Inc., (1995) (ISBN 1-56081-569-8).

To facilitate the examination of various embodiments of this discovery, the following explanations of specific terms are presented.

Action potential: a rapidly propagating electrical signal that travels along the axon of a neuron and above the surface membrane of many muscle and glandular cells. In axons, they are short, pass at a constant speed and maintain a constant amplitude. Like all electrical signals of the central nervous system, the action potential is a change in the membrane potential caused by the flow of ions passing through the membrane channels. In one embodiment, the action potential is a regenerative wave of sodium permeability.

Animal: living multicellular vertebrate organisms in a category that includes, for example, mammals and birds. The term mammal includes both humans and non-human mammals. Similarly, the term “subject” includes both human and veterinary facilities.

Anorexia: Lack or loss of appetite caused by food. In one embodiment, anorexia is the result of anorexia nervosa. This is an eating disorder that mainly affects women, usually at the beginning of puberty. It is characterized by a refusal to maintain normal minimum body weight, a strong fear of weight gain or obesity, and anxiety about the appearance of the body, which results in a feeling that some parts of the body are getting fat or become fat even in cases of severe exhaustion, unjustified self-confidence assessment of body mass or shape and causes amenorrhea. Concomitant symptoms often include denial of the disease and immunity to psychotherapy, symptoms of depression, significantly reduced libido and obsession (obsession), or specific behavior in relation to food, such as storing food. The disorder is divided into two subtypes - the limiting type, in which weight loss is achieved mainly through diet or exercise, and the type associated with overeating / cleansing of the body, in which the behavior of overeating or cleansing also occurs regularly.

Antagonist: A substance whose activity trend is the abolition of another, as in the case of an agent that binds a cell receptor without causing a biological reaction, blocking the binding of substances that could cause such reactions.

Appetite: Natural desire or desire for food. In one embodiment, the appetite is measured by examination to assess the desire for food. Increased appetite, as a rule, leads to increased eating behavior.

Appetite suppressants: Compounds that reduce the desire for food. Commercially available appetite suppressants include, but are not limited to, ampepramone (diethylpropion), phentermine, mazindol, and phenylpropanolamine phenfluramine, dexfenfluramine, and fluoxetine.

Binding: A specific interaction between two molecules such that two molecules interact. Binding can be specific and selective, with one molecule having an advantage in binding compared to another molecule. In one embodiment, the specific binding is identified by the dissociation constant (K _d ).

Body Mass Index (BMI): A mathematical formula for measuring body mass, sometimes also called the Quetelet Index. BMI is calculated by dividing body weight (in kg) by height ² (in m ² ). According to modern standards, for men and women, BMI 20-24.9 kg / m ^{2 is} taken as "normal". In one embodiment, BMI greater than 25 kg / m ² may be used to identify obesity in a subject. I degree obesity corresponds to BMI 25-29.9 kg / m ² . Grade II obesity corresponds to a BMI of 30-40 kg / m ² , and grade III obesity corresponds to a BMI of more than 40 kg / m ² (see Jequier, Am. J. Clin. Nutr., 45: 1035-47, (1987)). . Ideal body weight will vary between species and individuals depending on growth, physique, bone structure and gender.

c-fos: Cell homologue of the viral oncogen v-fos found in FBJ (Finkel-Biskis-Jinkins) and FBR mouse osteosarcoma viruses (MSV). The human fos gene maps to chromosome 14q21-q31. Human fos is identified as TIS-28. It is believed that c-fos plays an important role in signal transduction, proliferation, and differentiation of cells. It is a nuclear protein that, in combination with other transcription factors (e.g. jun), acts as a trans-activating regulator of gene expression. C-fos is an immediate early response gene that is believed to play a key role in the early response of cells to growth factors. C-fos is also involved in the control of cell growth and differentiation of embryonic hematopoietic cells and nerve cells. The coding sequences of amino acids and nucleic acids of human c-fos are known (for example, see Verma et al., Cold Spring Harb. Symp. Quant. Biol., 51: 949, (1986); GenBank, registration numbers K00650 and M 16287, but information on the Internet).

Cachexia: General physical exhaustion and malnutrition, which are often associated with a chronic painful process. Cachexia is often noted in patients with cancer, AIDS or other diseases. Cachexia includes, but is not limited to: 1) cancer cachexia observed in cases of cancer; 2) cardiac cachexia - depletion due to heart disease, which is usually caused by a combination of increased calorie expenditure and reduced calorie consumption or use; 3) fluoride cachexia observed with fluorosis; 4) pituitary cachexia; 5) cachexia associated with insufficiency of the pituitary gland - a complex of symptoms resulting from the general deprivation of the pituitary gland, including tuberculosis, loss of sexual function, atrophy of the glands associated with the pituitary gland, bradycardia, hypothermia, apathy and coma; 6) malarial cachexia - a group of physical signs of a chronic nature, which are caused by previous attacks of severe malaria; 7) mercurialism observed in chronic mercury poisoning; 8) pituitary cachexia (Simmonds disease); 9) lead cachexia observed in chronic lead poisoning; 10) suprarenal cachexia associated with Addison's disease; and 11) uremic cachexia associated with other systemic symptoms of chronic renal failure.

Calories or calorie intake: The number of calories (energy) consumed by an individual.

Calorie: A unit of measure for food. A standard calorie is defined as 4.184 absolute joules or the amount of energy needed to raise the temperature of one gram of water from 15 to 16 ° C (or 1/100 of the amount of energy needed to raise the temperature of one gram of water at a pressure of 1 atmosphere from 0 ° From up to 100 ° C. A food calorie is actually equal to 1000 standard calories (1 food calorie = 1 kilocalorie).

Conservative variation: Replacing one amino acid residue with another, biologically close residue. Examples of conservative variations include replacing one hydrophobic residue, such as isoleucine, valine, leucine or methionine, with another, or replacing arginine with lysine, or replacing one polar residue with another, such as replacing arginine with lysine, glutamic acid with aspartic acid or glutamine with asparagine, etc. . The term "conservative variation" also includes the use of a substituted amino acid instead of the unsubstituted starting amino acid, provided that antibodies formed to the substituted polypeptide are also immunoreactive with the unsubstituted polypeptide.

Non-limiting examples of conservative amino acid substitutions include the following substitutions:

Original balance Conservative substitutions Ala Ser Arg Lys Asn Gln his Asp Glu Cys Ser Gln Asn Glu Asp His Asn; Gln Ile Leu Val Leu Ile Val Lys Arg; Gln; Glu Met Leu; Ile Phe Met; Leu; Tyr Ser Thr Thr Ser Trp Tyr Tyr Trp; Phe Val Ile Leu

Depolarization: Increased cell membrane potential. Some stimuli reduce charge in the plasma membrane. They can be represented by electrical stimuli (which open potential-regulated channels), mechanical stimuli (which activate mechanically adjustable channels) or certain neurotransmitters (which open ligand-regulated channels). In each case, the facilitated diffusion of sodium into cells increases the resting potential at the point on the cell that creates the exciting postsynaptic potential (EPSP). Depolarization can also be created by reducing the frequency of inhibitory postsynaptic currents (IPSCs), which, using inhibitory neurotransmitters, promote the influx of chloride ions into the cell, creating IPSC. When the potential is increased to a threshold voltage (approximately 50 mV in mammalian neurons), an action potential is generated in the cell.

Diabetes: Inability of cells to transport endogenous glucose through membranes due to both endogenous insulin deficiency and / or a defect in insulin sensitivity. Diabetes is a chronic carbohydrate, protein, or fat metabolism disorder due to insufficient insulin secretion or insulin resistance to the target tissue. There are two main forms of diabetes: insulin-dependent diabetes mellitus (IDDM, type I) and non-insulin-dependent diabetes mellitus (NIDDM, type II), which differ in etiology, pathology, genetics, age of onset of the disease and treatment.

Both major forms of diabetes are characterized by the inability to deliver insulin in the amount and at the exact time that is necessary to control glucose homeostasis. Type I diabetes or insulin-dependent diabetes mellitus (IDDM) is caused by β-cell destruction, which results in insufficient levels of endogenous insulin. Type II diabetes or non-insulin-dependent diabetes is caused by both a defect in the body's sensitivity to insulin and a relative deficiency in insulin production.

Food Absorption: The amount of food consumed by a person. The absorption of food can be measured by volume or mass. In one embodiment, the absorption of food is the food consumed by a person. In another embodiment, the absorption of food is represented by the amount of proteins, fats, carbohydrates, cholesterol, vitamins, minerals, or any other food components consumed by a person. The term "protein uptake" refers to the amount of protein consumed by a person. Similarly, the terms “fat absorption”, “carbohydrate absorption”, “cholesterol absorption”, “vitamin absorption” and “mineral absorption” refer to the amount of protein, fat, carbohydrate, cholesterol, vitamins or minerals consumed by a person.

Hyperpolarization: Decreased cell membrane potential. Inhibitory neurotransmitters inhibit the transmission of nerve impulses through hyperpolarization. This type of hyperpolarization is called inhibitory postsynaptic potential (IPSP). Although the cell is not charged to a threshold voltage, a hyperpolarized cell needs a stronger stimulus to reach the threshold value.

Postsynaptic inhibition current: A current that inhibits the electrophysiological parameter of a postsynaptic cell. The potential of the postsynaptic cell can be analyzed to determine the effect on the presynaptic cell. In one embodiment, the postsynaptic cell is maintained in a state of voltage fixation and postsynaptic currents are recorded. If necessary, antagonists of other classes of currents can be added. In one specific non-limiting example, excitatory channel or receptor blockers are added to detect GABAergic IPSCs. Then, the instantaneous frequency is determined over time.

In one embodiment, the implementation of IPSCs is a measure of the frequency of GABA exit from a neuron containing NPY. Since NPY-containing neurons secrete GABA to POMC neurons, measuring the frequency of IPSCs is a measure of the inhibitory signal that POMC neurons receive and can be used to evaluate the effect of a PYY agonist.

Membrane potential: The electrical potential of the inside of a cell relative to its environment, such as the solution in which the cell is located. A competent specialist in this field can easily determine the membrane potential of a cell, for example, using accepted techniques using whole cells. Cell activation is associated with less negative membrane potentials (e.g., shifts from about -50 mV to about -40 mV). These changes in potential increase the probability of occurrence of action potentials and, thus, lead to an increase in the frequency of action potentials.

The repetition rate of action potentials can be determined using many approaches, such as using the accepted technique based on whole cells or, for example, using whole-cell configurations with a perforated area or configurations attached to cells. In each event, it is not the absolute value of the voltage or current that is estimated, but the frequency of fast deviations characterizing the action potentials, which is defined as a function of time (as a result, this frequency is the instantaneous frequency indicated in "bins"). This time component may be related to the time at which a compound, such as a PYY agonist, is introduced into a container to analyze the effect of the compound, such as a PYY agonist, on the pulse rate of the action potential.

Neuropeptide Y (NPY): A 36 amino acid peptide that is a neuropeptide identified in the human brain. NPY is believed to be an important regulator in both the central and peripheral nervous systems and affects a wide range of physiological parameters, including effects on psychomotor activity, food absorption, central endocrine secretion, and cardiovascular vasoactivity. High concentrations of NPY are found in the sympathetic nerves, which provide the coronary, cerebral and renal vasculature and play a role in vasoconstriction. NPY binding centers have been identified in many tissues, including the spleen, intestinal membranes, brain, smooth muscle of the aorta, kidneys, testicle, and placenta. In addition, binding centers are described in a number of rat and human cell lines.

The neuropeptide Y receptor (NPY) is close in structure / activity to the pancreatic peptide family. This family includes NPY, which is predominantly synthesized in neurons, the YY peptide (PYY), which is predominantly synthesized in the endocrine cells of the intestine, and the pancreatic polypeptide (PP), which is predominantly synthesized in the endocrine cells of the pancreas. These 36 amino acid peptides have a compact helical structure including an amino acid structure called the “PP fold” in the middle of the peptide.

NPY binds to several receptors, including receptors Y1, Y2, Y3, Y4 (PP), Y5, Y6 and Y7. These receptors are recognized by binding affinities, pharmacology and sequence (if known). Most, if not all, of these receptors are G-protein-coupled receptors. It has generally been suggested that the Y1 receptor is postsynaptic and mediates many of the known peripheral functions of neuropeptide Y. This receptor was originally described as having low affinity for the C-terminal fragments of neuropeptide Y, such as fragment 13-36, but it interacts with the full-length neuropeptide Y and the YY peptide with equal affinity (for example, see PCT publication WO 93/09227) .

Pharmacologically, the Y2 receptor differs from Y1 in that it exhibits affinity for the C-terminal fragments of neuropeptide Y. The Y2 receptor is most often differentiated by the affinity of neuropeptide Y (13-36), although fragment 3-36 of neuropeptide Y and peptide YY have increased affinity and selectivity ( see Dumont et al., Society for Neuroscience Abstracts, 19: 726, (1993)). Signal transmission through both receptors, Y1 and Y2, is associated with inhibition of adenylate cyclase. It has also been found that binding to the Y-2 receptor reduces intracellular calcium levels at the synapse by selectively inhibiting N-type calcium channels. In addition, the Y-2 receptor, like the Y1 receptors, differently binds to secondary messengers (see US Patent No. 6355478). Y2 receptors are found in many parts of the brain, including the hippocampus, substantia nigra, thalamus (optic tubercle), hypothalamus, and brain stem. Cloned Y2 receptors of humans, mice, monkeys and rats (for example, see US Patent No. 6420352 and US Patent No. 6355478).

A Y2 receptor agonist is a peptide, small molecule, or chemical compound that predominantly binds to the Y2 receptor and stimulates the transmission of an intracellular signal. In one embodiment, the Y2 receptor agonist binds to the receptor with equal or greater affinity than NPY. In another embodiment, an agonist selectively binds to a Y2 receptor compared to binding to another receptor.

A competent specialist in this field can easily determine the value of the dissociation constant (K _d ) of a given compound. This value depends on the selectivity of the test compound. For example, compounds with K _d less than 10 nM are generally considered a promising drug candidate. However, a compound that has a lower affinity but is selective for a particular receptor may also be a good candidate drug substance. In one specific non-limiting example, an assay, such as a competitive assay, is used to determine if a compound is of interest as a Y2 receptor agonist. Assays used to evaluate neuropeptide Y receptor antagonists are also well known in the art (see US Patent No. 5284839, which is incorporated herein by reference, and Walker et al., Journal of Neurosciences, 8: 2438-2446 , (1988)).

Normal daily diet: Average food intake for an individual of a given species. A normal daily diet can be expressed in units of calorie intake, protein intake, carbohydrate intake and / or fat intake. For a person, a normal daily diet typically provides the following: approximately 2,000, approximately 2,400, or approximately 2,800 to a significantly larger number of calories. In addition, a normal daily human diet typically includes from about 12 g to about 45 g of protein, from about 120 g to about 610 g of carbohydrates, and from about 11 g to about 90 g of fat. A low-calorie diet for humans would not exceed about 85% and preferably about 70% of normal calorie intake.

In animals, calorie and nutrient requirements vary depending on the type and size of the animal. For example, in cats, the total calorie / pound intake, as well as the percentage distribution of protein, carbohydrates and fats, changes with the cat's age and reproductive status. However, the general norm for cats is 40 cal / lb / day (18.2 cal / kg / day). From about 30% to about 40% should be protein, from about 7% to about 10% should be from carbohydrates, and from about 50% to about 62.5% should come from fat intake. A competent specialist in this field can easily determine the normal daily diet of an individual of any kind.

Obesity: A condition in which excess body fat may suggest a risk to the subject’s health (see Barlow and Dietz, Pediatrics, 102: E29, (1998); National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI ), Obes. Res. 6 (suppl. 2): 51S-209S, (1998)). Excess body fat is the result of an imbalance in energy consumption and energy expenditure. In one embodiment, the BMI is used to measure obesity. In one embodiment, a BMI of 25.0 kg / m ² to 29.9 kg / m ² is overweight, while a BMI of 30 kg / m ² is obese.

In another embodiment, a waist circumference is used to assess obesity. In this embodiment, a waist circumference in men of 102 cm or more is considered obesity, while in women obesity is considered a waist circumference of 89 cm or more. There is strong evidence that obesity affects morbidity and mortality in subjects. For example, an obese subject has an increased risk of developing heart disease, non-insulin-dependent diabetes (type 2), hypertension, stroke, cancer (e.g., cancer of the endometrium, breast, prostate and colon), dyslipidemia, gall bladder disease, sleep apnea, decreased fertility and osteoarthritis and others (see article Lyznicki et al., Am. Fam. Phys., 63: 2185, (2001)).

Overweight: A subject whose body weight exceeds its ideal body weight. An overweight subject may be obese, but not necessarily obese. In one embodiment, the overweight subject is any subject that wishes to reduce its body weight. In another embodiment, the overweight subject is a subject with BMI from 25.0 kg / m ² to 29.9 kg / m ² .

Pancreatic polypeptide: A 36 amino acid peptide produced by the pancreas that has homology with PYY and NPY.

Peripheral administration: Introduction outside the central nervous system. Peripheral administration does not include direct administration to the brain. Peripheral administration includes, but is not limited to, intravascular, intramuscular, subcutaneous, inhalation, oral, rectal, transdermal, or intranasal administration.

Polypeptide: A polymer in which monomers are amino acid residues that are linked by amide bonds. When the amino acids are α-amino acids, either the L-optical isomer or the D-optical isomer can be used, with L-isomers being preferred. The terms "polypeptide" or "protein", as used in this context, are intended to set any amino acid sequence and include modified sequences, such as glycoproteins. The term "polypeptide" is specifically intended to cover natural proteins, as well as those proteins that are obtained by recombinant or synthetic means. The term “polypeptide fragment” refers to a portion of a polypeptide, for example, such a fragment that represents at least one sequence involved in binding to a receptor. The term "functional fragments of a polypeptide" refers to all fragments of a polypeptide that retain the activity of the polypeptide. Biologically functional peptides may also include fusion proteins in which the peptide of interest is fused to another peptide that does not reduce its desired activity.

PYY: YY polypeptide peptide obtained or isolated from any species. So, PYY includes a full-length human polypeptide (as presented in SEQ ID NO: 1) and species variations of PYY, containing, for example, PYY of mouse, hamster, chicken, cattle, rat and dog (SEQ ID NOS: 5-12) . In one embodiment, the implementation of the PYY agonists do not include NPY. PYY also includes PYY _3-36 . A "PYY agonist" is any compound that binds to a receptor that specifically binds PYY and causes the effect of PYY. In one embodiment, the PYY agonist is a compound that affects food absorption, calorie intake, or appetite and / or that exhibits specific binding in a Y receptor assay or competes for binding to PYY, as in a competitive binding assay for labeled PYY. PYY agonists include, but are not limited to, compounds that bind to the Y2 receptor.

Virtually purified: A polypeptide that is substantially free of other proteins, lipids, carbohydrates, or other materials with which it is bound in vivo. For example, a polypeptide may be at least 50%, 80%, or 90% purified from other proteins, lipids, carbohydrates, or other materials with which it is bound in vivo.

Therapeutically effective amount: A dose sufficient to prevent development, or to regress the disorder, or to alleviate the symptom or symptom of the disorder, or which may produce the desired result. In some embodiments, a therapeutically effective amount of PYY or an agonist thereof is an amount sufficient to suppress or stop the increase in body weight, or an amount sufficient to reduce appetite, or an amount sufficient to reduce calorie intake, or absorb food, or increase energy expenditure.

Unless otherwise explained, all technical and scientific terms used in this context have the same meaning as usually means an ordinary specialist in the field to which this discovery relates. Terms in the singular include objects in the plural, unless the context clearly indicates otherwise. Similarly, the word “or” provides for the inclusion of “and”, unless the context clearly indicates otherwise. In addition, it should be understood that all base sizes or amino acid sizes, as well as all molecular weights or molecular weights, data for nucleic acids and polypeptides are approximate and are given for description. Although methods and materials similar or equivalent to those described in this context can be used in the implementation or testing of this description, suitable methods and materials are described below. The term “comprises” means “includes”. All publications, patent applications, patents, and other references mentioned in this context are incorporated by reference in their entirety. In case of conflict, this description, including explanations of the terms, will serve as a check. In addition, the materials, methods and examples are for illustration only and are not intended to be limiting.

Ways to change food intake, appetite, calorie intake, and energy expenditure

In this context, a method for reducing food intake by peripherally administering to a subject a therapeutically effective amount of PYY or a PYY agonist is described. In one embodiment, the administration of a PYY or a PYY agonist results in a decrease in either the total weight or the total volume of food. In another embodiment, the administration of PYY or an agonist thereof results in a decrease in the absorption of food components, such as a decrease in the intake of lipids, carbohydrates, cholesterol or proteins. In any of the methods described herein, as a preferred compound, PYY _3-36 may be administered. This discovery includes a method of modifying eating behavior and the corresponding use of PYY or an agonist thereof for the preparation of a medicament for the purposes presented in this context, and includes the use of PYY as a means to reduce calories, reduce food intake, or reduce appetite or increase energy consumption in a subject.

Also provided in this context is a method of reducing calorie intake by peripherally administering to a subject a therapeutically effective amount of PYY or a PYY agonist. In one embodiment, the total calorie intake is reduced by peripherally administering a therapeutically effective amount of PYY. In other embodiments, the implementation reduces the calorie intake associated with the intake of specific food components, such as, but not limited to, the intake of lipids, carbohydrates, cholesterol or proteins.

In a further embodiment, a method for reducing appetite by administering a therapeutically effective amount of PYY or an agonist thereof is described in this context. Appetite can be measured by any means known to a competent person skilled in the art. For example, decreased appetite can be determined using psychological assessment. In this embodiment, the administration of PYY results in a change in hunger, satiety and / or satiety. Hunger can be appreciated by any means known to a competent person skilled in the art. In one embodiment, hunger is assessed using psychological tests, such as assessing hunger and sensory perception, using a questionnaire such as, but not limited to, a Visual Analog Score (VAS) questionnaire (see Examples section). ) In one specific, non-limiting example, hunger is assessed by answering questions regarding the desire for food, drinks, future eating, nausea, and sensations related to smell or taste.

In a further embodiment, a method for changing a subject's energy metabolism is described in this context. The method includes peripherally administering to the subject a therapeutically effective amount of PYY or an agonist thereof in order to thereby alter energy expenditure. Energy burning occurs in all physiological processes. The body can directly change the level of energy consumption by modulating the effectiveness of these processes or by changing the number and nature of the processes. For example, during digestion, the body spends energy on the movement of food through the intestine, as well as the breakdown of food and intracellular processes, while the efficiency of cellular metabolism can be changed so as to obtain more or less heat. In a further embodiment, in this context, a method is described for any and all manipulations in the arcuate core system presented with this application, which consistently change the absorption of food and in the opposite way change the energy expenditure. Energy costs are the result of cell metabolism, protein synthesis, metabolic rate, and calorie use. Thus, in this embodiment, the peripheral administration of PYY leads to increased energy expenditures and reduced calorie utilization. In one embodiment, a therapeutically effective amount of PYY or an agonist thereof is administered to a subject to thereby increase energy expenditure.

In a number of embodiments, PYY (e.g., PYY _3-36 ) or an agonist thereof is used to control body weight, as well as to treat, reduce or prevent obesity, in particular any one or more of the following: preventing and reducing body weight gain, induction and stimulating weight loss and reducing obesity as measured by a body mass index. In addition, the description relates to the use of PYY or an agonist thereof as an active ingredient in the manufacture of a medicament to reduce calorie intake, reduce food intake or reduce appetite or increase energy consumption in a subject. The following description relates to a method of maintaining a desired body weight, maintaining a desired body mass index, desirable appearance and good health using PYY and its agonist.

The subject may be any subject, including human and mammalian veterinary facilities. So, the subject can be represented by a person or can be a non-human primacy, an agricultural animal such as a pig, cattle and bird, a sports animal or a domestic animal such as dogs, cats, horses, hamsters, rodents, or animals - zoo dwellers such as lions, tigers or bears.

Obesity is currently a difficult to treat, chronic, almost incurable metabolic disorder. A therapeutic drug effective in reducing body weight in obese individuals could have a strong positive effect on their health. Thus, a subject can be represented without limitation by a listed subject that is overweight or obese. In one embodiment, the subject has or is at risk of developing a disorder in which obesity or being overweight is a risk factor for the disorder. Disorders of interest include, but are not limited to, cardiovascular disease (including, but not limited to, hypertension, atherosclerosis, congestive heart failure, and dyslipidemia), stroke, gallbladder disease, osteoarthritis, sleep apnea, reproductive disorders, such as, but not limited to, polycystic ovary syndrome, forms of cancer (e.g., cancer of the breast, prostate, colon, endometrium, kidney and esophagus), varicose veins, acanthosis nigricans, eczema, intolerant physical activity, insulin resistance, hypertension, hypercholesterolemia, cholelithiasis, osteoarthritis, orthopedic injuries, insulin resistance (such as, but not limited to, with type 2 diabetes and X syndrome) and thromboembolic disease (see Kopelman, Nature, 404: 635-43; Rissanen et al., British Med. J., 301,835, (1990)).

Other concomitant disorders also include depression, anxiety, panic attacks, migraine headaches, PMS (premenstrual syndrome), chronic pain, fibromyalgia, insomnia, impulsivity, obsessive-compulsive disorder, and myoclonus. Obesity is a recognized risk factor in terms of increasing the likelihood of complications during general anesthesia (see, for example, Kopelman, Nature, 404: 635-43, (2000)). It reduces life expectancy and poses a serious risk of developing concomitant diseases of the above.

Other diseases or disorders associated with obesity are birth defects (maternal obesity is associated with an increased likelihood of neural tube defects), carpal tunnel syndrome (CTS), chronic venous insufficiency (CVI), daytime sleepiness, deep vein thrombosis (DVT) , end stage kidney disease (ESRD), gout, temperature disorders, impaired immune response, respiratory failure, infertility, liver disease, lower back pain, birth complications and gynecological complications, pancreatitis t, as well as abdominal hernias, acanthosis nigricans, endocrine disorders, chronic hypoxia and hypercapnia, dermatological effects, elephantiasis, gastroesophageal reflux, calcaneal spurs, swelling of the lower extremities, mammomegaly (causing big problems such as pain from a bra strap, damage skin, pain in the cervix, persistent smell and infections in the skin folds under the breast, etc.), a large mass of the front wall of the abdomen (abdominal panniculitis, accompanied by frequent panniculitis, difficulty walking, frequent infections , Odor, difficulty dressing, pain in the lower back), muscular-skeletal diseases, pseudotumor brain (or benign intracranial hypertension), and sliding hiatal hernia.

This description of the invention relates to the treatment, prevention, amelioration or alleviation of conditions or disorders caused, complicated or aggravated due to the relatively high availability of nutrients. By “condition or disorder that can be alleviated by reducing the availability of calories (or nutrients)” is meant any condition or disorder in a subject that is either caused, complicated or aggravated by the relatively high availability of nutrients, or can be alleviated by reducing the availability of nutrients, for example, by reducing the absorption of food. The invention may also be useful for subjects with insulin resistance, glucose intolerance, or any form of diabetes mellitus (for example, type 1, 2 or gestational diabetes).

These conditions or disorders are disorders associated with increased calorie intake, insulin resistance or glucose intolerance, and include, but are not limited to, obesity, diabetes, including type 2 diabetes, eating disorders, insulin resistance syndromes, and Alzheimer's disease.

In another embodiment, the subject is a subject who wishes to reduce body weight, such as a female or male subject, who wishes to change their appearance. In yet another embodiment, the subject is a subject who wishes to reduce the feeling of hunger, such as, but not limited to: a person engaged in long-term work that requires a high level of concentration (for example, soldiers on active duty, air traffic controllers or truck drivers on long-distance routes, etc.).

The invention also relates to a method for controlling food intake in mammals using PYY or an antagonist thereof. The description of the invention also relates to a method of controlling body weight using PYY or an antagonist thereof, in particular any one or more of the following: stimulating, promoting and increasing weight gain, reducing, suppressing and preventing weight loss, as well as increasing body weight, measured using body mass index. In addition, the invention relates to a method of controlling any one or more of the following characteristics: appetite, satiety and hunger, in particular any one or more of the following signs: increasing, awakening and stimulating appetite, reducing, suppressing or preventing satiety and a feeling of satiety and increase, stimulation and intensification of hunger and hunger with PYY or PYY _3-36 .

Strengthening weight gain may be desirable for commercial reasons in animal husbandry. Thus, it is possible to use a PYY antagonist for humans, domestic animals and other objectively or subjectively valuable animals, for example horses. PYY antagonists can be used to stimulate appetite and enhance weight gain in case of poor appetite and weight loss or the possibility of weight loss. Specific non-limiting examples include the time of illness, the period after an accidental injury or trauma caused by surgical intervention (for example, after burns and, in particular, after severe burns), the recovery period, the elderly, as well as anorexia and bulimia and other conditions causing exhaustion. Stimulation of appetite and weight gain may be especially desirable in specific conditions, for example, with cachexia (exhaustion) in AIDS and in cancer patients.

A suitable administration format may be best determined by the subject or medical practitioner. In one embodiment, the pharmaceutical compositions, which include PYY or an agonist or antagonist thereof, will preferably be formulated in a unit dosage form suitable for individual dosage administration. An effective amount of PYY or an agonist thereof can be administered in a single dose or in multiple doses, for example, daily during the course of treatment. In one embodiment, PYY is administered when its effect is desired (e.g., appetite suppression, reduced food intake, or reduced calorie intake). In another embodiment, PYY or an analogue thereof is administered shortly before the moment when its effect is desired, for example, but not limited to, in about 10 minutes, in about 15 minutes, in about 30 minutes, in about 60 minutes, in about 90 minutes or about 120 minutes before the time when the effect is desired. In another embodiment, the drug release time is used.

In one embodiment, the therapeutically effective amount of PYY or an agonist thereof is administered in a single pulse dose, as a bolus dose, or as pulse doses administered over a long period of time. Thus, at pulse doses, a PYY bolus is used, followed by a period of time in which PYY is not administered to the subject, followed by a second bolus. In specific non-limiting examples, pulse doses of PYY are administered during the daily course, during the weekly course, or during the monthly course.

A therapeutically effective amount of PYY or an agonist thereof will depend on the molecule used, the subject to be treated, the severity and type of disease and route of administration. For example, a therapeutically effective amount of PYY or an agonist thereof may vary from about 0.01 μg / kg (kg) body weight to about 1 g / kg body weight, for example, from about 1 μg to about 5 mg / kg body weight, or from about 5 mcg to approximately 1 mg / kg body weight. In another embodiment, PYY or an agonist thereof is administered to a subject in a dose of from 0.5 to 135 picomoles (pmol) / kg body weight or about 72 pmol / kg body weight. In one specific non-limiting example, about 5 to about 50 nmol is administered by subcutaneous injection, for example, from about 2 to about 20 nmol, or about 10 nmol is administered by subcutaneous injection. A competent person skilled in the art can easily determine the exact dose based on the activity of the particular compound used (such as the PYY polypeptide or its agonist), age, body weight, gender and physiological state of the subject. The dose of the agonist may be molar equivalent to a therapeutically effective dose of PYY or PYY _3-36 .

Compositions or pharmaceutical compositions may be administered by any route, including intravenous, intraperitoneal, subcutaneous, sublingual, transdermal, intramuscular, oral, external administration, as well as administration through mucous membranes or pulmonary inhalation. The compositions used in the invention can easily be obtained in the form of preparations suitable for parenteral (including intravenous, intramuscular and subcutaneous), nasal or oral administration. The term "parenteral", as used in this context, refers to methods of administration, which include intravenous, intramuscular, intraperitoneal, intrathoracic, subcutaneous and intraarticular injection and infusion. PYY, including PYY _3-36 , a PYY agonist, or a PYY antagonist, can be administered subcutaneously. It is well known in the art that subcutaneous injections are easy to do for yourself.

In some cases, it will be convenient to obtain a PYY or a PYY agonist and another agent that reduces the absorption of food, reduces the level of glucose in the plasma or changes the level of lipids in the plasma, in one composition or solution for co-administration. In other cases, it is more appropriate to administer an additional agent separately from said PYY or a PYY agonist.

A suitable administration format may be best determined by the practitioner individually for each patient. Various pharmaceutically acceptable carriers and their composition are described in a monograph on standard preparations, for example, Remington's Pharmaceutical Sciences Handbook, ed. E.W. Martin. See also Wang Y.J. and Hanson M.A., Journal of Parenteral Science and Technology, Technical Report No. 10, Add. 42: 2S, (1988).

PYY, PYY agonists and PYY antagonists used in the methods described herein can be prepared as parenteral compositions, for example, for injection or infusion. Preferably, when they are suspended in an aqueous carrier, for example, in an isotonic buffer solution at a pH of from about 3.0 to about 8.0, preferably at a pH from about 3.5 to about 7.4, 3.5 to 6.0, or from 3.5 to about 5.0. Suitable buffers include sodium citrate citric acid and sodium phosphate phosphoric acid, as well as acetate / acetic acid buffers. A sustained release form or depot preparation may be used in slow release, with therapeutically effective amounts of the drug being delivered into the bloodstream for many hours or days after percutaneous injection or delivery.

Since PYY and agonists are amphoteric, they can be used in the form of free bases, salts formed by the addition of acid or metal salts. Of course, the salts must be pharmaceutically acceptable, and they will include metal salts, in particular alkali and alkaline earth metal salts, for example, potassium and sodium salts. There is a wide range of pharmaceutically acceptable salts obtained by the addition of acids. These products are readily prepared by methods well known to those skilled in the art.

For use by doctors, the compositions may be presented in unit dosage form containing an amount of PYY or a PYY agonist with or without the addition of another active ingredient, for example, an agent that reduces food absorption, reduces plasma glucose or changes plasma lipids. The introduction can be started when suppression of nutrient availability, absorption of food, decrease in body weight, blood glucose or plasma lipids is desirable, for example, at the first signs of development of symptoms of disorders related to body weight or soon after obesity, sugar is diagnosed diabetes or insulin resistance syndrome.

Therapeutically effective amounts of PYY or a PYY agonist to reduce nutrient availability are those that suppress appetite at a desired level. As will be apparent to those skilled in the art, the effective amount of the therapeutic agent will vary depending on many factors, including the activity of the particular compound, the patient’s age and body weight, the patient’s physical condition, blood sugar, and body weight that they want to receive , and other factors. Likewise, therapeutically effective amounts of the PYY antagonist to obtain increased nutrient availability are amounts that increase appetite to the desired level. As will be apparent to those skilled in the art, the effective amount of a given therapeutic agent will also vary depending on many factors, including the activity of the particular compound, the patient’s age and body weight, the patient’s physical condition, blood sugar, and body weight want to get other factors. The introduction can be started when increasing the availability of nutrients, absorption of food, body weight, glucose level or a decrease in plasma lipids, for example, but not limited to, at the first signs of the development of symptoms of anorexia or at the beginning of weight loss in AIDS is desirable.

The optimal preparation and route of administration of PYY, PYY agonists and PYY antagonists to a patient depends on factors known in the art, such as the particular disease or disorder, desired effect and patient type. Although PYY, PYY agonists, and PYY antagonists are generally used to treat humans, they can also be used to treat similar or identical diseases in other vertebrates, such as other primates, farm animals such as pigs, cattle and poultry, as well as sports animals and pets such as horses, dogs and cats.

As a pharmaceutical preparation, PYY, PYY agonists and PYY antagonists of the invention can be administered directly by any suitable route, including parenteral, intranasal, oral or by absorption through the skin. The competitive route of administration of each of the agents will depend, for example, on the animal’s medical history.

For parenteral administration in one embodiment, PYY, PYY agonists and PYY antagonists can be prepared mainly by mixing them at the desired degree of purity in a unitary dosage form (solution, suspension or emulsion) with a pharmaceutically acceptable carrier, i.e. a carrier that is nontoxic to recipients at the used doses and concentrations and is compatible with other ingredients of the drug. The term “pharmaceutically acceptable carrier” refers to a non-toxic solid, semi-solid or liquid excipient, diluent, encapsulating material or adjuvant of any type. For example, it is preferable when the preparation does not include oxidizing agents and other compounds known as damaging PYY and PYY agonists.

Typically, formulations are prepared by uniformly and intimately contacting a PYY, a PYY agonist or a PYY antagonist with liquid carriers or finely divided solid carriers or both forms of carriers. Then, if necessary, the desired preparation is created from the product. Preferably, the carrier is provided for parenteral administration, more preferably a solution isotonic with respect to the blood of the recipient. Examples of such carriers include water, saline, Ringer's solution, and dextrose solution. In addition, non-aqueous vehicles such as fatty (non-volatile) oils and ethyl oleate, as well as liposomes, are used in this context.

PPY, PYY antagonists, and PYY agonists are also suitably administered using sustained release systems. Suitable examples of PYY and sustained release PYY agonists include suitable polymeric materials (such as, for example, semi-permeable polymer bases in the form of molded products, for example films or microcapsules), suitable hydrophobic materials (such as, for example, an emulsion in an acceptable oil), or ion exchange resins and poorly soluble derivatives (such as a poorly soluble salt). The compositions of PPY, a PYY antagonist and a delayed release PYY agonist can be administered orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (for example, in the form of powders, ointments, gels, drops or transdermal patch), cheek (in buccal or spray form for mouth or nose.

Slow release bases include polylactides (see U.S. Patent No. 3773919, EP 58481), copolymers of L-glutamic acid and γ-ethyl-L-glutamate (see Sidman et al., Biopolymers, 22: 547-556, ( 1983)), poly- (2-hydroxyethyl methacrylate) (see articles by Langer et al., J. Biomed. Mater. Res., 15: 167-277, (1981); Langer, Chem. Tech., 12: 98- 105, (1982), ethylene vinyl acetate (see article Langer et al., Id.) Or poly-D - (-) - 3-hydroxybutyric acid (EP 133988).

PPY, PYY antagonists and sustained release PYY agonists include liposomal PPY and PYY agonists (see mainly Langer, Science, 249: 1527-1533, (1990); section written by Treat et al. In the monograph “Liposomes in Infectious Therapy” diseases and cancer "(" Liposomes in the Therapy of Infectious Disease and Cancer "), edited by Lopez-Berestein and Fidler, Liss, New York, c. 317-327 and 353-365, (1989)). Liposomes containing the peptide and peptide analogs of PPY are prepared by methods that are known per se: see patent application DE 3218121; articles by Epstein et al., Proc. Natl. Acad. Sci. U.S.A. 82: 3688-3692, (1985); Hwang et al., Proc. Natl. Acad. Sci. U.S.A., 77: 4030-4034, (1980); Patent Applications EP 52322, EP 36676, EP 88046, EP 143949, EP 142641, Japanese Patent Application No. 83-118008; U.S. Patent No. 4,485,045, U.S. Patent No. 4544545 and patent application EP 102324. Typically, liposomes are represented by the type of small (approximately 200-800 angstroms) single-layer liposomes in which the lipid content exceeds approximately 30 mol% of cholesterol, the selected ratio is adjusted to obtain optimal characteristics.

Administration formulations may be suitably prepared to provide a controlled release of PYY, PYY antagonists and PYY agonists. For example, the pharmaceutical compositions may be in the form of particles containing a biodegradable polymer and / or a polysaccharide gelling and / or biodegradable polymer, an amphiphilic polymer, an agent that modifies the separation properties of particle surfaces and a pharmacologically active substance. These compositions exhibit certain biocompatibility properties that allow for a controlled release of the active substance. See U.S. Patent No. 5700486.

In yet a further embodiment, PPY, PYY antagonists, and PYY agonists are delivered by pump (see articles Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng., 14: 201, (1987); Buchwald et al., Surgery, 88: 507, (1980); Saudek et al., N. Engl. J. Med., 321: 574, (1989)) or by continuous subcutaneous infusion, for example, using a mini pump. A reservoir with an intravenous solution may also be used. The key factor in choosing the appropriate dose is the result, measured by reducing the total body weight or the ratio of fat to fat free of fat, or by other criteria for determining the outcome of the fight or preventing the development of obesity or preventing the development of conditions associated with obesity, which the practical doctor considers suitable. Other controlled output systems are discussed in the Langer review (see Science, 249: 1527-1533, (1990)).

In another aspect of the invention, PPY, PYY antagonists, and PYY agonists are delivered using an implant pump, as described, for example, in US Pat. 6436091, US Patent No. 5,939,380 and U.S. Pat. 5993414.

Implantable drug infusion devices are used to provide patients with a continuous, long-term dosage or infusion of a drug substance or other therapeutic agent. In general, such devices can be classified as active and passive.

Active devices for programmed drug infusion are characterized by a pump or dosing system, which are used to deliver the drug to the patient system. An example of such a current active drug infusion device is the Medtronic SynchroMed ™ programmable pump. These pumps typically include a drug reservoir, a peristaltic pump to pump the drug out of the reservoir, and a catheter opening for transferring the drug pumped out of the reservoir to the patient. These devices usually have a battery to power the pump, as well as an electronic module to control the flow rate provided by the pump. The Medtronic SynchroMed ™ pump also includes an antenna for remote programming of the pump. In contrast, passive drug infusion devices do not have a pump, but their action is based on a drug reservoir under pressure, which ensures drug delivery. Thus, these devices are usually smaller and cheaper than active devices. An example of such a device includes Medtronic IsoMed ™. This device delivers a drug substance to a patient through the force that a pressure reservoir provides through a flow control unit.

An implanted pump can be completely implanted under the patient’s skin, thereby eliminating the need for a subcutaneous catheter. These implanted pumps may provide the patient with a PYY, a PYY antagonist, or a PYY agonist with a constant or programmable delivery rate, for example, giving pulse doses at or around a meal. Constant speed or programmable speed pumps are based on either phase change or peristaltic technology. When a constant, unchanging delivery rate is required, a constant-speed pump is well suited for an implantable long-acting drug delivery system. If changes in diffusion rate are contemplated, a programmable pump can be used instead of a constant speed pump system. Osmotic pumps are much smaller than other constant speed pumps or programmable pumps because the infusion rate can be very slow. An example of such a pump is presented in US Pat. 5728396.

When administered orally, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional methods with pharmaceutically acceptable excipients, such as binding agents (for example, pre-gelatinized corn starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or acidic calcium phosphate); sliding components (e.g. magnesium stearate, talc or silica); disintegrating components (e.g. potato starch or sodium starch glycolate) or wetting agents (e.g. sodium lauryl sulfate). Tablets may be coated using methods well known in the art. Liquid preparations for oral administration may, for example, take the form of solutions, syrups or suspensions, or may be presented as a dry product for reconstitution with water or another suitable vehicle before use. These liquid preparations can be prepared by conventional methods using pharmaceutically acceptable additional components, such as suspending agents (for example, sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (for example, lecithin or gum arabic); non-aqueous vehicles (e.g., almond oil, fatty esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid). If necessary, the preparations may also contain buffering salts, flavoring agents, coloring agents and sweeteners.

For administration by inhalation, the compounds used according to this invention are conveniently delivered in the form of an aerosol represented by pressure packs or a nebulizer using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoropentane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit is determined using a valve delivering a metered amount. For use in an inhaler or insufflation device, capsules and cartridges, for example from gelatin, may be prepared containing a powder mixture of the compound and a suitable powder base such as lactose or starch.

The compounds may also be formulated as rectal compositions, such as suppositories or delayed enemas, for example, containing accepted suppository bases, such as cocoa butter or other glycerides.

In addition to the above preparations, the compounds can be prepared as depot preparations. These long-acting drugs can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be prepared in combination with suitable polymeric or hydrophobic materials (for example, as an emulsion with an acceptable oil) or ion exchange resins or as poorly soluble derivatives, for example, a poorly soluble salt.

Formulations of pharmaceutical compositions that contain PYY as an active agent, or an agonist thereof, or a PYY antagonist, as described herein, will typically include the appropriate solid or liquid carrier depending on the particular route of administration chosen. Pharmaceutically acceptable carriers and excipients used in this description of the invention are generally accepted. For example, parenteral preparations usually contain injectable liquids, which are pharmaceutically and physiologically acceptable liquid carriers, such as water, physiological saline, other balanced saline solutions, aqueous dextrose, glycerin, and the like. Excipients that may be included are, for example, other proteins, such as human serum albumin or plasma preparations. If desired, the pharmaceutical composition intended for administration may also contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate. Other medical and pharmaceutical agents may also be administered, for example, other appetite suppressing agents or protease inhibitors. Competent specialists in this field are known or will be obvious modern methods of preparing these dosage forms.

The dosage form of the pharmaceutical composition will be determined by the selected route of administration. For example, in addition to injectable fluids, inhalation forms, suppositories and oral preparations may be used. Pharmaceutical compositions may be prepared using conventional mixing, granulating, stirring with honey or syrup, dissolving or lyophilization processes.

Oral formulations may be liquid (e.g., syrups, solutions or suspensions) or solid (e.g., powders, pills, tablets or capsules). For example, pharmaceutical compositions for oral administration can be prepared by combining the active ingredient with one or more solid carriers, optionally granulating the resulting mixture and, if desired, treating the mixture or granules into which additional excipients are added to form tablets or dragee cows, if necessary.

Suitable carriers include excipients such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and binders such as starches, for example corn, wheat or potato starch, methyl cellulose , hydroxypropyl methyl cellulose, carboxymethyl cellulose sodium salt and / or polyvinyl pyrrolidone and / or, if desired, disintegrants, such as the above starches, cross-linked polyvinyl pyrrolidone, and ginovaya acid or a salt thereof such as sodium alginate. Additional excipients include fluid conditioning agents and lubricating components, for example silicic acid, talc, stearic acid or its salts, such as magnesium or calcium stearate and / or polyethylene glycol or its derivatives.

Compositions for parenteral administration include suitable aqueous solutions of the active ingredient in a water-soluble form, for example, in the form of a water-soluble salt or aqueous injection suspensions, which contain viscosity-modifying substances, for example, sodium carboxymethyl cellulose, sorbitol and / or dextran, and, if desired, stabilizers. The active ingredient, optionally together with excipients, may also be in the form of a lyophilisate and may be reconstituted prior to parenteral administration by the addition of suitable solvents. Solutions such as those used for parenteral administration, for example, can also be used as infusion solutions.

For inhalation, PYY, either an agonist or antagonist of PYY, is administered as an aerosol or dispersion in a carrier. In one specific non-limiting example, PYY or an agonist thereof is administered in an aerosol from a conventional valve, such as, but not limited to, a metering valve, through an aerosol adapter, also known as a control valve. A suitable liquid carrier may also be incorporated into the preparation, such as, but not limited to, air, a hydrocarbon, including n-butane, propane, isopentane, etc., or a propellant, such as, but not limited to, fluorocarbon. Optionally, a stabilizer may also be introduced and / or porous particles may be included for deep lung delivery (for example, see US Patent No. 6447743).

The preparation of compounds with poor solubility in aqueous systems requires the use of solubilizing agents such as ionic surfactants, cholates, polyethylene glycol (PEG), ethanol and other agents that may cause unwanted effects when used for inhalation. In addition, treatment requiring efficient delivery of the lower lobes of the lung to the alveoli may be hindered by the use of certain irritating components, such as chlorofluorocarbons, in the preparation, and it should include the minimum number of necessary doses. Alternatively, in order to avoid such limitations, liposomes or hydrophobic particles can be used. In one embodiment, the sustained release aerosol preparation is based on the use of aerosol droplet particles of a size of about 1-2.1 microns or a size of less than 1 micron. Small particles of aerosol liposomes and combinations of liposomes and drug substances for use in medicine have been described previously (for example, see patent application EP 87309854.5).

In one embodiment, a therapeutically effective amount of PYY or an agonist thereof is administered along with a therapeutically effective amount of another agent, such as, but not limited to, an additional appetite suppressant. A specific non-limiting example of an additional appetite suppressing agent includes ampepramone (diethylpropion), phentermine, macindol and phenylpropanolamine, fenfluramine, dexphenfluramine and fluoxetine. PYY and / or a PYY agonist can be administered simultaneously with an additional appetite suppressant or they can be administered sequentially. So, in one embodiment, PYY is prepared and administered with an appetite suppressing agent as a single dose.

Additionally, in this context, a method for treating obesity is described. The method comprises administering to a subject with an obesity a therapeutically effective amount of PYY or a PYY agonist. A PYY agonist may have activity that, in at least one aspect, absorption of food or emptying of the stomach, is greater than NPY activity. PYY and / or a PYY agonist can be administered peripherally, for example, in a single or divided dose. Suitable single or divided doses include, but are not limited to, from 1 μg to about 5 mg, or from about 0.01 μg / kg to about 500 μg / kg / dose. A subject may have insulin resistance or glucose intolerance, or both of these disorders. In addition to obesity, the subject may suffer from diabetes.

A method of reducing food intake is also described in this context. The method comprises administering to a subject with an obesity a therapeutically effective amount of PYY or a PYY agonist. A PYY agonist may have activity that, in at least one aspect, absorption of food or emptying of the stomach, is greater than NPY activity. PYY and / or a PYY agonist can be administered peripherally, for example, in a single or divided dose. Suitable single or divided doses include, but are not limited to, from 1 μg to about 5 mg, or from about 0.01 μg / kg to about 500 μg / kg / dose. The subject may suffer from type II diabetes or be overweight.

In this context, a method for improving the lipid profile of a subject is described. The method comprises administering to the subject an effective amount of PYY or a PYY agonist. Improving the lipid profile includes, but is not limited to, at least one aspect - lowering cholesterol, lowering triglycerides and increasing levels of HDL-cholesterol (cholesterol containing high density lipoproteins). PYY and / or a PYY agonist can be administered peripherally, for example, in a single or divided dose. Suitable single or divided doses include, but are not limited to, from 1 μg to about 5 mg, or from about 0.01 μg / kg to about 500 μg / kg / dose. A PYY agonist may have activity that, in at least one aspect, absorption of food or emptying of the stomach, is greater than NPY activity.

In another embodiment, a method for alleviating a condition or disorder that can be alleviated by reducing the availability of nutrients is described in this context. The method comprises administering to the subject a therapeutically effective amount of PYY or a PYY agonist. Relevant violations include any of the above violations. PYY and / or a PYY agonist can be administered peripherally, for example, in a single or divided dose. Suitable single or divided doses include, but are not limited to, from 1 μg to about 5 mg, or from about 0.01 μg / kg to about 500 μg / kg / dose. A PYY agonist may have activity that, in at least one aspect, absorption of food or emptying of the stomach, is greater than NPY activity. Suitable doses also include doses that increase the concentration of PYY and / or its agonist well above the base concentration of PYY, such as, but not limited to, a dose mimicking the concentration of PPY (or its agonist) in serum after a meal. Thus, in one embodiment, PYY or an agonist thereof is administered to achieve a level or obtain an effect of reducing calorie intake, food intake or appetite, equal to reducing calorie intake, food intake or appetite, or increasing energy expenditures caused by PYY _3-36 occurring after food intake. Specific non-limiting examples of dosages include, but are not limited to, dosages that produce an effect demonstrated when serum PYY levels are from about 40 pM to about 50 pM or from about 40 pM to about 45 pM or to about 43 pM.

For all methods described in this context, the dose of PYY or PYY _3-36 can be based on physiological levels observed after a meal. Normal PYY _3-36 levels in the circulatory system are approximately 8 pmol / L, typically rising to approximately 40-60 pmol / L after a meal. PYY agonists can be used in similar doses. A single dose may be administered once a day, or divided doses may be used (see above). Since it is shown that PYY _{3-36 is} effective up to 12 and even up to 24 hours after administration, it is possible to administer only two or even only once / day.

In one embodiment, when administered peripherally, PYY, including PYY _3-36 , exhibits effects at physiological levels. Other intestinal hormones (for example, GLP) with peripheral administration show an effect only at levels higher than physiological and have side effects. When using PYY3-36 side effects are not observed. Regardless of theory, PYY _3-36 does not act on Y2 receptors in the brain that could cause side effects. Without limiting, it should be noted that the next advantage of PYY _3-36 is that PYY _3-36 does not increase blood pressure. The effects of PYY _3-36 are long lasting and last 24 hours. It is described that recipients noted a decrease in appetite during this period and a decrease in food intake by about one third.

In one specific non-limiting example, PYY _3-36 is administered at a dose of about 1 nmol or more, 2 nmol or more, or 5 nmol or more. In this example, the dose of PYY _3-36 , as a rule, does not exceed 100 nmol, for example, the dose is 90 nmol or less, 80 nmol or less, 70 nmol or less, 60 nmol or less, 50 nmol or less, 40 nmol or less, 30 nmol or less, 20 nmol or less, 10 nmol. For example, the dosage range may comprise any combination of any limits of the indicated lower doses with any limits of the indicated higher doses. Thus, exemplary non-limiting dose ranges include a dose of PYY _3-36 , which may be in the range from 1 to 100 nmol, from 1 to 90 mol, from 1 to 80 nmol. Exemplary non-limiting dose ranges include from 2 to 100 nmol, from 2 to 90 nmol, for example from 2 to 80 nmol and the like, from 5 nmol to 100 mol, from 5 nmol to 90 nmol, from 5 nmol to 80 nmol, and etc. An example of a dose that can be administered is a dose of from about 5 to about 50 nmol, such as, but not limited to, from about 2 to about 20 nmol, for example about 10 nmol. The selected dose may be administered, for example, by injection, in particular as a subcutaneous injection. In one embodiment, a dose of PYY or PYY _{3-36 of} 0.143 nmol (1/7 mol) / kg is administered to achieve a dose similar to the PYY level after a meal.

When using PYY or an agonist thereof, the dose is preferably the molar equivalent of the dose of PYY _3-36 , as described above. Doses can be calculated according to a subject, such as a subject with a body weight of 70 to 75 kg. It is easy for a person skilled in the art to determine the exact dose based on the activity of the particular compound used (such as a polypeptide or PYY agonist), as well as the age, body weight, gender and physiological state of the subject.

As presented in this context, a natural peptide, PYY or PYY _3-36 can be used to achieve a physiological effect. This results in minimal side effects and, if necessary, provides a long-lasting effect. The dose of PYY or PYY _3-36 may be based on physiological levels observed after a meal. Normal levels of PYY _3-36 in the circulatory system are approximately 8 pmol / L, typically rising to approximately 40 to 60 pmol / L after a meal. PYY (e.g., PYY _3-36 ) and agonists may be used in similar doses.

Thus, various methods of using PYY or an agonist or antagonist thereof, as described above, can be carried out in a method for treating a mammal of a subject that needs this treatment, or can be presented in the manufacture of drugs for such treatment. PYY (for example, PYY _3-36 , or an agonist or antagonist thereof, should be administered in an amount effective to achieve the claimed subject. Some of the solutions described are methods of treatment, for example, treatment of obesity. However, other solutions do not relate to treatment and are part of maintaining healthy lifestyle or serve for cosmetic purposes.

PYY agonists

The PYY agonist used in the methods of this invention is a molecule that binds to a receptor that specifically binds PYY and produces the effect of PYY. Methods for analyzing binding to PYY receptors and obtaining a response in a cell having a PYY receptor are known in the art. A specific analysis aimed at detecting a PYY agonist is presented in this context. Thus, in one embodiment, the PYY agonist binds to a neuron containing NPY in an arcuate nucleus, resulting in an electrophysiological effect on a neuron containing NPY. As presented in this context, forms a synapse with POMC neurons. Thus, the electrophysiological effect against a neuron containing NPY can cause a further electrophysiological effect on the POMC neuron. In one specific non-limiting example, administration of a PYY agonist results in hyperpolarization of the membrane potential of the POMS neuron. In another specific non-limiting example, administration of a PYY agonist leads to an increase in IPSCs in the POMC neuron.

In another embodiment, the PYY agonists do not include NPY. Suitable PYY agonists are molecules that bind neurons containing NPY but do not cross the blood-brain barrier. The neurons of the arcuate nucleus affected by PYY are not protected by the blood-brain barrier, and as a result, they are easily achievable for peripherally administered molecules. In addition, other parts of the brain that express the Y2 receptor are protected by the blood-brain barrier. Regardless of theory, agents capable of binding to the Y2R of the arcuate nucleus, but not crossing the blood-brain barrier after peripheral administration, are likely to be effective.

In one embodiment, the PYY agonist is a compound that affects food absorption, calorie intake, or appetite and / or that specifically binds in a Y receptor assay or competes for PYY binding, as in a competitive binding assay using labeled PYY. PYY agonists include, but are not limited to, compounds that bind to the Y2 receptor.

PYY and agonists used in the methods described in this context include, but are not limited to, polypeptides containing or, alternatively, consisting of a sequence of amino acids of PPY and its agonists, for example, their mutants, inversions, fragments and / or variants. Options include deletions, insertions, inversions, repeats and substitutions, for example, conservative substitutions and non-conservative substitutions (see, for example, Tables 1 and 2 below). More than one amino acid (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.) can be removed, or introduced or replaced with another amino acid. As a rule, conservative substitutions are substitutions of one amino acid for another among the aliphatic amino acids Ala, Val, Leu and Il; interchange of Ser and Thr containing hydroxyl residues, interchange of acid residues Asp and Glu, interchange of amide residues Asn and Gln, interchange of basic residues Lys and Arg, interchange of aromatic residues Phe and Tyr and interchange of small amino acids Ala, Ser, Thr, Met and Gly. Guidance on how to make phenotypically silent amino acid substitutions is presented in Bowie et al., Science, 247: 1306-1310, (1990).

As another example, polypeptide fragments may contain a continuous series of deleted residues from the amino (N) - or carboxyl (C) -terminal or both ends (see, for example, Tables 1 and 2 below). From the N-terminus, C-terminus or both ends, any number of amino acids in the range from 1 to 24 can be removed.

Moreover, agonistic polypeptides may also include, but are not limited to, polypeptides containing or, alternatively, consisting of internal deletions of the amino acid sequences of PPY and / or its agonist (see, for example, Tables 1 and 2 below). These deletions can be represented by deletions from one or more amino acid residues (e.g., one, two, three, four, five, six, seven, eight, nine, ten, etc.) and can start from any position of the amino acid (e.g. second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, etc.). In addition, the polypeptides corresponding to this description of the invention may contain one or more internal deletions. These deletions are possible in PPY, NPY and PP.

Also considered are agonistic peptides represented by PPY, NPY and / or PP chimeras that have high affinity and / or selectivity for the Y2 receptor. These chimeras may contain amino acid substitutions with one or more amino acids (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.) from PPY, NPY and / or PP, their variants, mutants and / or deletions of one or more amino acids (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.) from the second PPY, NPY or PP, their variants, mutants and / or deletions. These substitutions may begin with the position of any amino acid (e.g., second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, etc.).

Preferably, when the peptide has selectivity for the Y2 receptor. This means that it binds to Y2 with a higher affinity than other receptors such as Y1, Y2, Y3, Y4, Y5 and Y6. In another embodiment, the peptide has selectivity for receptors Y2 and Y5 relative to receptors Y1, Y3, Y4 and Y6.

Other polypeptide fragments are fragments containing the structural or functional domain of the polypeptides corresponding to this description of the invention. These fragments include amino acid residues that comprise a polyproline type II helix (residues 1-8), a β-fold (residues 9-14), an amphipathic α-spiral (residues 15-32) and / or a C-terminal fold structure (residues 33 -36). See Kirby et al., J. Med. Chem., 36: 385-393, (1993).

In addition, this description of the invention includes the use of a polypeptide or agonist containing or, alternatively, consisting of an amino acid sequence of species variants of PPY, NPY and PP (see Table 1 below) and / or their mutants and fragments.

Fusion proteins are also contemplated, wherein the PYY or PYY agonist will be fused to another protein or polypeptide (fusion partner) using recombinant methods known in the art. Alternatively, such a fusion protein can be obtained by synthesis using any known method. As the fusion partner, any known peptide or protein can be used (for example, serum albumin, carbon hydride, glutathione S-transferase or thioredoxin, etc.). Preferred fusion partners will not have harmful in vivo biological activity. These fusion partners can be constructed by binding the carboxy terminus of the fusion partner to the amino terminus of the PYY peptide or agonist, or vice versa. Optionally, a cleavable linker region linking the PYY or PYY agonist to the fusion partner can be used, and it can be cleaved in vivo, resulting in the release of the active form of PYY or PYY agonist. Examples of these cleavage sites include, but are not limited to, DDDDY linker sites (SEQ ID NO: 330), GPR (SEQ ID NO: 331), AGG (SEQ ID NO: 332), and HPFHL (SEQ ID NO 333), which may cleaved by enterokinase, thrombin, ubiquitin-releasing enzyme and renin, respectively. See, for example, U.S. Patent No. 6410707.

In addition, PYY agonists represented by Y2-specific peptide NPY agonists, as described in US Pat. 5026685, US Patent No. 5574010, US Patent No. 5604203, US Patent No. 5696093, US Patent No. 6046167. (See below.)

Preferred PPY agonists are described in this context as follows.

TABLE 1 PYY: Variations among species of organisms YY peptide Amino acid sequence Person YPIKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY (SEQ ID NO: 1) Rat YPAKPEAPGEDASPEELSRYYASLRHYLNLVTRQRY (SEQ ID NO: 5) Pig YPAKPEAPGEDASPEELSRYYASLRHYLNLVTRQRY (SEQ ID NO: 6) The guinea pig YPSKPEAPGSDASPEELARYYASLRHYLNLVTRQRY (SEQ ID NO: 7) Frog YPPKPENPGEDASPEEMTKYLTALRHYINLVTRQRY (SEQ ID NO: 8) Ramp YPPKPENPGDDAAPEELAKYYSALRHYINLITRQRY (SEQ ID NO: 9) Shark YPPKPENPGEDAPPEELAKYYSALRHYINLITRQRY (SEQ ID NO: 10) Lamprey FPPKPDNPGDNASPEQMARYKAAVRHYINLITRQRY (SEQ ID NO: 11) Petromyzon MPPKPDNPSPDASPEELSKYMLAVRNYINLITRQRY (SEQ ID NO: 12) Neuropeptide Y Amino acid sequence Person YPSKPDNPGEDAPAEDMARYYSALRHYINLITRQRY (SEQ ID NO: 2) Rat YPSKPDNPGEDAPAEDMARYYSALRHYINLITRQRY (SEQ ID NO: 13) Rabbit YPSKPDNPGEDAPAEDMARYYSALRHYINLITRQRY (SEQ ID NO: 14) Dog YPSKPDNPGEDAPAEDMARYYSALRHYINLITRQRY (SEQ ID NO: 15) Pig YPSKPDNPGEDAPAEDLARYYSALRHYINUTRQRY (SEQ ID NO: 16) Cow YPSKPDNPGEDAPAEDLARYYSALRHYINLITRQRY (SEQ ID NO: 17) Sheep YPSKPDNPGDDAPAEDLARYYSALRHYINLITRQRY (SEQ ID NO: 18) The guinea pig YPSKPDNPGEDAPAEDMARYYSALRHYINLITRQRY (SEQ ID NO: 19) Birds YPSKPDSPGEDAPAEDMARYYSALRHYINLITRQRY (SEQ ID NO: 20) Bull frog YPSKPDNPGEDAPAEDMAKYYSALRHYINLITRQRY (SEQ ID NO: 21) Goldfish YPTKPDNPGEGAPAEELAKYYSALRHYINLITRQRY (SEQ ID NO: 22) Shark YPSKPDNPGEGAPAEDLAKYYSALRHYINLITRQRY (SEQ ID NO: 23) Lamprey PPNKPDSPGEDAPAEDLARYLSAVRHYINLITRQRY (SEQ ID NO: 24)

Pancreatic Polypeptide Amino acid sequence Person ASLEPEYPGDNATPEQMAQYAAELRRYINMLTRPRY (SEQ ID NO: 3) Sheep APLEPVYPGDNATPEQMAQYAADLRRYINMLTRPRY (SEQ [D NO: 25) Pig APLEPVYPGDDATPEQMAQYAAELRRYINMLTRPRY (SEQ ID NO: 26) Dog APLEPVYPGDDATPEQMAQYAAELRRYINMLTRPRY (SEQ ID NO: 27) Cat APLEPVYPGDNATPEQMAQYAAELRRYINMLTRPRY (SEQ ID NO: 28) Cow APLEPEYPGDNATPEQMAQYAAELRRYINMLTRPRY (SEQ ID NO: 29) Rat APLEPMYPGDYATHEQRAQYETQLRRYINTLTRPRY (SEQ ID NO: 30) Mouse APLEPMYPGDYATPEQMAQYETQLRRYINTLTRPRY (SEQ ID NO: 31) The guinea pig APLEPVYPGDNATPEQQMAQYAAEMRRYINMLTRPRY (SEQ ID NO: 32) Chicken GPSQPTYPGDDAPVEDLIRFYNDLQQYLNWTRHRY (SEQ ID NO: 33) Alligator TPLQPKYPGDGAPVEDLIQFYNDLQQYLNWTRPRF (SEQ ID NO: 34) Bull frog APSEPHHPGDQATPDQLAQYYSDLYQYITFITRPRF (SEQ ID NO: 35)

See Beck-Sickinger A.G., Jung G., Biopolymers (Biopolymers), 37: 123-142, (1995).

TABLE 2 PEPTIDE - PYY AGONIST Peptide Sequence PPY (3-36) (person)

IKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY (SEQ ID NO: 334)

Reference: see articles by Eberlein et al., Peptides, 10: 797-803, (1989), Grandt et al., Peptides, 15 (5): 815-20, (1994).

Variations of PPY (3-36)

N-terminal PYY deletions, including but not limited to: PYY (26-36), PYY (25-36), PYY (24-36), PYY (23-36), PYY (22-36), PYY (21- 36), PYY (20-36), PYY (19-36), PYY (18-36), PYY (17-36), PYY (16-36), PYY (15-36), PYY (14-36 ), PYY (13-36), PYY (12-36), PYY (11-36), PYY (10-36), PYY (9-36), PYY (8-36), PYY (7-36) , PYY (6-36), PYY (5-36), PYY (4-36), PYY (3-36).

Reference: See, for example, articles by Balasubramaniam et al., Pept. Res. 1 (1): 32-5, (Sept.-Oct. 1998); Liu et al., J. Gastrointest. Surg., 5 (2): 147-52, (March-April 2001).

Peptide Sequence

NPY (person)

YPSKPDNPGEDAPAEDMARYYSALRHYINLITRQRY (SEQ ID NO: 2)

Reference: see article by Tatemoto et al., Proc. Natl. Acad. Sci. U.S.A., 79: 5485-9, (1982).

NPY variations

N-terminal NYY deletions, including but not limited to: NPY (26-36), NPY (25-36), NPY (24-36), NPY (23-36), NPY (22-36), NPY ( 21-36), NPY (20-36), NPY (19-36), NPY (18-36), NPY (17-36), NPY (16-36), NPY (15-36), NPY (14 -36), NPY (13-36), NPY (12-36), NPY (11-36), NPY (10-36), NPY (9-36), NPY (8-36), NPY (7- 36), NPY (6-36), NPY (5-36), NPY (4-36), NPY (3-36).

Reference: see, for example, articles by Gehlert et al., Proc. Soc. Exp.Biol. Med., 218: 7-22, (1998); Sheikh et al., Am. J. Physiol., 261: 0701-15, (November 1991).

Internal deletions, including but not limited to: (1-4) -Aca- (14-36) pNPY, (1-4) -Aca- (15-36) pNPY, (1-4) -Aca- (16-36 )] pNPY, (1-4) -Aca- (17-36) pNPY, (1-4) -Aca- (18-36) pNPY, (1-4) - (31-36) pNPY11, (1- 4) -Aca- (31-36) pNPY, (4-1) - (31-36) pNPY, (4-1) -Aca- (31-36) pNPY, (4-1) D- (31- 36) pNPY, (4-1) D-Aca- (31-36) pNPY.

Link: see article Fournier et al., Mol. Pharmacol., 45 (1): 93-101, (Jan. 1994).

Additional internal deletion mutants, including but not limited to: des AA ^10-17 -NPY, des AA ^10-17 , Ac- [D-Lys ⁹ (∈-Ac-Ala)] NPY, des AA ^10-17 , Ac [D-Lys ⁹ [∈-Ac-Ala)] NPY, des AA ^10-17 [Ala ^7.21 ] NPY, des-AA ^10-17 [Cys ^7.21 ] NPY, des-AA ^10-17 [Glu ⁷ , Lys ²¹ ] NPY, [des AA ^11-17 [D-Lys ¹⁰ (∈-Ac), Cys ^7.21 ] NPY, des AA ^10-17 [D-Cys ⁷ , D-Lys ( ∈-Ac), Cys ²¹ ] NPY, des AA ^10-17 [D-Cys ⁷ , Lys ⁹ (∈-Ac), Cys ²¹ ] NPY, des AA ^10-17 [Cys ^7.21 , Pro ³⁴ ] NPY, des AA ^10-17 [Asp ⁷ , Dpr ²¹ , Pro ³⁴ ] NPY, des AA ^10-17 [Glu ⁷ , Lys ²¹ , Pro ³⁴ ] NPY, des AA ^10-17 [Cys ^7.21 , Leu ³¹ , Pro ³⁴ ] NPY, des AA ^10-20 [Cys ^7.21 , Pro ³⁴ ] NPY, des AA ^10-17 [Cys ^2.27 ] NPY, des AA ^10-17 [Cys ² , D -Cys ²⁷ ] NPY.

Reference: see article Kirby et al., J. Med. Chem., 38: 4579-86, (1995).

A cyclic NPY agonist, including but not limited to: [Lys25-Glu29] NPY (Ac-25-36), [Glu25-Lys29] NPY (Ac-25-36), [Lys26-Glu31] NPY (Ac-25-36) , [Glu27-Lys31] NPY (Ac-25-36), [Lys28-Glu32] NPY (Ac-25-36), [Lys27-Glu34] NPY (Ac-25-36).

Link: see article Rist et al., Eur. J. Biochem. 247: 1019-1028, (1997).

Substitutions of D-amino acids: [D-Tyr ¹ ] NPY, [D-Pro ² ] NPY, [D-Ser ³ ] NPY, [D-Lys ⁴ ] NPY, [D-Pro ⁵ ] NPY, [D-Asp ⁶ ] NPY, [D-Asn ⁷ ] NPY, [D-Pro ⁸ ] NPY, [D-Ala ⁹ ] NPY, [D-Glu ¹⁰ ] NPY, [D-Asp ¹¹ ] NPY, [D-Ala ¹² ] NPY , [D-Pro ¹³ ] NPY, [D-Ala ¹⁴ ] NPY, [D-Glu ¹⁵ ] NPY, [[D-Asp ¹⁶ ] NPY, [D-Leu ¹⁷ ] NPY, [D-Ala ¹⁸ ] NPY, [D-Arg ¹⁹ ] NPY, [D-Tyr ²⁰ ] NPY, [D-Tyr ²¹ ] NPY, [D-Ser ²² ] NPY, [D-Ala ²³ ] NPY, [D-Leu ²⁴ ] NPY, [D -Arg ²⁵ ] NPY, [[D-His ²⁶ ]] NPY, [D-Tyr ²⁷ ] NPY, [D-Ile ²⁸ ] NPY, [D-Asn ²⁹ ] NPY, [D-Leu ³⁰ ] NPY, [D -Ile ³¹ ] NPY, [D-Thr ³² ] NPY, [D-Arg ³³ ] NPY, [D-Gln ³⁴ ] NPY, [D-Arg ³⁵ ] NPY, [D-Tyr ³⁶ ] NPY, [D-Tyr ¹ , D-Pro ² ] NPY, [D-Ser ³ , D-Lys ⁴ ] NPY, [D-Pro ⁵ , D-Asp ⁶ ] NPY, [D-Asn ⁷ , D-Pro ⁸ ] NPY, [D -Glu ¹⁰ , D-Asp ¹¹ ] NPY, [D-Asp ¹¹ , D-Ala ¹² ] NPY, [D-Pro ¹³ , D-Ala ¹⁴ ] NPY, [D-Glu ¹⁵ , D-Asp ¹⁶ ] NPY, [D-Met ¹⁷ , D-Ala ¹⁸ ] NPY, [D-Arg ¹⁹ , D-Tyr ²⁰ ] NPY, [D-Tyr ²¹ , D-Ser ²² ] NPY, [D-Ala ²³ , D-Leu ²⁴ ] NPY, [D-Arg ²⁵ , D-His ²⁶ ] NPY, [D-Tyr ²⁷ , D-Ile ²⁸ ] NPY, [D-Asn ²⁹ , D-Leu ³⁰ ] NPY, [D-Ile ³¹ , D-Thr ³² ] NPY, [D-Arg ³³ , D-Gln ³⁴ ] NPY, [D-Arg ³⁵ , D-Tyr ³⁶ ] NPY.

Reference: see articles by Kirby et al., J. Med. Chem., 36: 3802-08, (1993);

Grundemar et al., Regulatory Peptides, 62: 131-136, (1996).

Other agonists and analogues of NPY

Peptide Sequence

NPY (3-36)

SKPDNPGEDAPAEDMARYYSALRHYINLITRQRY (SEQ ID NO: 335)

Ref: see Grandt et al., Regulatory Peptides, 67 (1): 33-7, (1996).

Peptide Sequence

N-Acetyl NPY (24-36)

LRHYINLITRQRY (SEQ ID NO: 213)

Reference: see article Potter et al., Eur. J. Pharmacol. 267 (3): 253-262, (May 17, 1994).

Peptide Sequence

N-Acetyl [Leu ²⁸ , Leu ³¹ ] NPY (24-36)

LRHYLNLLTRQRY (SEQ ID NO: 214)

Reference: see article Potter et al., Eur. J. Pharmacol. 267 (3): 253-262, (May 17, 1994).

Peptide Sequence

[Leu ²⁸ , Leu ³¹ ] NPY (24-36)

LRHYLNLLTRQRY (SEQ ID NO: 215)

Reference: see article Potter et al., Eur. J. Pharmacol. 267 (3): 253-262, (May 17, 1994).

Peptide Sequence

[Leu ¹⁷ , Gln ¹⁹ , Ala ²¹ , Ala ²² , Glu ²³ , Leu ²⁸ , Leu ³¹ ] NPY (13-36)

PAEDLAQYAAELRHYLNLLTRQRY (SEQ ID NO: 216)

Reference: see article Potter et al., Eur. J. Pharmacol. 267 (3): 253-262, (May 17, 1994).

Peptide Sequence

Cycle SS [Cys ²⁰ , Cys ²⁴ ] pNPY

SKPDNPGEDAPAEDMARCysACRHYINLITRQRY (SEQ ID NO: 315)

Link: see article Soil et al., Eur. J. Biochem., 268 (10): 2828-37, (May 2001).

Peptide Sequence

Cyclo- (28/32) -Ac- [Lys ²⁸ -Glu ³² ] - (25-36) -pNPY

RHYLNLIGRQRY (SEQ ID NO: 316)

Reference: Cabrele et al., J. Pept. Sci., 6 (3): 97-122, (March, 2000)

Peptide Sequence

Cycle- (27/31) -Ac- [Glu ²⁷ -Lys ³¹ ] - (25-36) -pNPY]

RHGLNLLGRQRY (SEQ ID NO: 317)

Reference: Cabrele et al., J. Pept. Sci., 6 (3): 97-122, (March, 2000)

Peptide Sequence

[Tyr ³² , Leu ³⁴ ] NPY (27-36)

YINLIYRLRY (SEQ ID NO: 318)

Reference: see article Leban et al., J. Med. Chem., 38: 1150-57, (1995).

Peptide Sequence

[Tyr ³² , Leu ³⁴ ] NPY (26-36)

HYINLIYRLRY (SEQ ID NO: 319)

Reference: see article Leban et al., J. Med. Chem., 38: 1150-57, (1995).

Peptide Sequence

[Tyr ³² , Leu ³⁴ ] NPY (25-36)

RHYINLIYRLRY (SED ID NO: 320)

Reference: see article Leban et al., J. Med. Chem., 38: 1150-57, (1995).

Peptide Sequence

[Leu ³¹ ] NPY (27-36)

YINLLYRQRY (SEQ ID NO: 321)

Reference: see article Leban et al., J. Med. Chem., 38: 1150-57, (1995).

Peptide Sequence

[Tyr ³² , Leu ³⁴ ] (1-4) -Ahr- (27-36) NPY

YPSL-Aha-YINLIYRLRY (SED ID NO: 322)

Reference: see article Leban et al., J. Med. Chem., 38: 1150-57, (1995).

Peptide Sequence

[Tyr ³² , Leu ³⁴ ] NPY (28-36)

INLIYRLRY (SEQ ID NO: 323)

Reference: see article Leban et al., J. Med. Chem., 38: 1150-57, (1995).

Peptide Sequence

PP (human)

ASLEPEYPGDNATPEQMAQYAAELRRYINMLTrpRY (SEQ ID NO: 3)

Reference: see article Kimmel et al., Endocrinology, 83: 1323-30, (1968).

RR variations

N-terminal deletions, including but not limited to: PP (26-36), PP (25-36), PP (24-36), PP (23-36), PP (22-36), PP (21-36 ), PP (20-36), PP (19-36), PP (18-36), PP (17-36), PP (16-36), PP (15-36), PP (14-36) , PP (13-36), PP (12-36), PP (11-36), PP (10-36), PP (9-36), PP (8-36), PP (7-36), PP (6-36), PP (5-36), PP (4-36), PP (3-36).

TABLE 3 Examples of conservative amino acid substitutions in PYY Single point mutations PYY (25-36) PEPTIDE SEQUENCE [Lys ²⁵ ] PPY (25-36) KHYLNLVTRQRY (SEQ ID NO: 36) [Thr ²⁷ ] PPY (25-36) RHTLNLVTRQRY (SEQ ID NO: 37) [Phe ²⁷ ] PPY (25-36) RHFLNLVTRQRY (SEQ ID NO: 38) [Ile ²⁸ ] PYY (25-36) RHYINLVTRQRY (SEQ ID NO: 39) [Val ²⁸ ] PYY (25-36) RHYVNLVTRQRY (SEQ ID NO: 40) [Gln ²⁹ ] PYY (25-36) RHYLQLVTRQRY (SEQ ID NO: 41) [Ile ³⁰ ] PYY (25-36) RHYLNIVTRQRY (SEQ ID NO: 42) [Val ³⁰ ] PYY (25-36) RHYLNVVTRQRY (SEQ ID NO: 43) [Ile ³¹ ] PYY (25-36) RHYLNLITRQRY (SEQ ID NO: 44) [Leu ³¹ ] PYY (25-36) RHYLNLLTRQRY (SEQ ID NO: 45) [Ser ³² ] PYY (25-36) RHYLNLVSRQRY (SEQ ID NO: 46) [Lys ³³ ] PYY (25-36) RHYLNLVTKQRY (SEQ ID NO: 47) [Asn ³⁴ ] PYY (25-36) RHYLNLVTKNRY (SEQ ID NO: 48) [Lys ³⁵ ] PYY (25-36) RHYLNLVTRQKY (SEQ ID NO: 49) [Thr ³⁶ ] PYY (25-36) RHYLNLVTRQRT (SEQ ID NO: 50) [Phe ³⁶ ] PYY (25-36) RHYLNLVTRQRF (SEQ ID NO: 51) Double point mutations PEPTIDE SEQUENCE [Lys ²⁵ , Thr ²⁷ ] PPY (25-36) KHTLNLVTRQRY (SEQ ID NO: 52) [Lys ²⁵ , Phe ²⁷ ] PPY (25-36) KHFLNLVTRQRY (SEQ ID NO: 53) [Lys ²⁵ , Ile ²⁸ ] PPY (25-36) KHYINLVTRQRY (SEQ ID NO: 54) [Lys ²⁵ , Val ²⁸ ] PPY (25-36) KHYVNLVTRQRY (SEQ ID NO: 55) [Lys ²⁵ , Gln ²⁹ ] PPY (25-36) KHYLQLVTRQRY (SEQ ID NO: 56) [Lys ²⁵ , Ile ³⁰ ] PPY (25-36) KHYLNIVTRQRY (SEQ ID NO: 57) [Lys ²⁵ , Val ³⁰ ] PPY (25-36) KHYLNVVTRQRY (SEQ ID NO: 58) [Lys ²⁵ , Ile ³¹ ] PPY (25-36) KHYLNLITRQRY (SEQ ID NO: 59) [Lys ²⁵ , Leu ³¹ ] PPY (25-36) KHYLNLLTRQRY (SEQ ID NO: 60) [Lys ²⁵ , Ser ³² ] PPY (25-36) KHYLNLVSRQRY (SEQ ID NO: 61) [Lys ²⁵ , Lys ³³ ] PPY (25-36) KHYLNLVTKQRY (SEQ ID NO: 62) [Lys ²⁵ , Asn ³⁴ ] PPY (25-36) KHYLNLVTRNRY (SEQ ID NO: 63)

[Lys ²⁵ , Lys ³⁵ ] PPY (25-36) KHYLNLVTRQKY (SEQ ID NO: 64) [Lys ²⁵ , Thr ³⁶ ] PPY (25-36) KHYLNLVTRQRT (SEQ ID NO: 65) [Lys ²⁵ , Phe ³⁶ ] PPY (25-36) KHYLNLVTRQRF (SEQ ID NO: 66) [Thr ²⁷ , Ile ²⁸ ] PPY (25-36) RHTINLVTRQRY (SEQ ID NO: 67) [Thr ²⁷ , Val ²⁸ ] PPY (25-36) RHTVNLVTRQRY (SEQ ID NO: 68) (Thr ²⁷ , Gln ²⁹ ] PPY (25-36) RHTLQLVTRQRY (SEQ ID NO: 69) [Thr ²⁷ , Ile ³⁰ ] PPY (25-36) RHTLNIVTRQRY (SEQ ID NO: 70) [Thr ²⁷ , Val ³⁰ ] PPY (25-36) RHTLNVVTRQRY (SEQ ID NO: 71) [Thr ²⁷ , Ile ^3l ] PPY (25-36) RHTLNUTRQRY (SEQ ID NO: 72) [Thr ²⁷ , Leu ³¹ ] PPY (25-36) RHTLNLLTRQRY (SEQ ID NO: 73) (Thr ²⁷ , Ser ³² ] PPY (25-36) RHTLNLVSRQRY (SEQ ID NO: 74) [Thr ²⁷ , Lys ³³ ] PPY (25-36) RHTLNLVTKQRY (SEQ ID NO: 75) [Thr ²⁷ , Asn ³⁴ ] PPY (25-36) RHTLNLVTRNRY (SEQ ID NO: 76) [Thr ²⁷ , Lys ³⁵ ] PPY (25-36) RHTLNLVTRQKY (SEQ ID NO: 77) [Thr ²⁷ , Thr ³⁶ ] PPY (25-36) RHTLNLVTRQRT (SEQ ID NO: 78) [Thr ²⁷ , Phe ³⁶ ] PPY (25-36) RHTLNLVTRQRF (SEQ ID NO: 79) [Phe ²⁷ , lle ²⁸ ] PPY (25-36) RHFINLVTRQRY (SEQ ID NO: 80) [Phe ²⁷ , Val ²⁸ ] PPY (25-36) RHFVNLVTRQRY (SEQ ID NO: 81) [Phe ²⁷ , Gln ²⁹ ] PPY (25-36) RHFLQLVTRQRY (SEQ ID NO: 82) [Phe ²⁷ , Ile ³⁰ ) PPY (25-36) RHFLNIVTRQRY (SEQ ID NO: 83) [Phe ²⁷ , Val ³⁰ ] PPY (25-36) RHFLNVVTRQRY (SEQ ID NO: 84) [Phe ²⁷ , Ile ³¹ ] PPY (25-36) RHFLNLITRQRY (SEQ ID NO: 85) [Phe ²⁷ , Leu ³¹ ] PPY (25-36) RHFLNLLTRQRY (SEQ ID NO: 86) [Phe ²⁷ , Ser ³² ] PPY (25-36) RHFLNLVSRQRY (SEQ ID NO: 87) [Phe ²⁷ , Lys ³³ ] PPY (25-36) RHFLNLVTKQRY (SEQ ID NO: 88) [Phe ²⁷ , Asn ³⁴ ] PPY (25-36) RHFLNLVTRNRY (SEQ ID NO: 89) [Phe ²⁷ , Lys ³⁵ ] PPY (25-36) RHPLNLVTRQKY (SBQ ID NO: 90) [Phe ²⁷ , Thr ³⁶ ] PPY (25-36) RHFLNLVTRQRT (SEQ ID NO: 91) [Phe ²⁷ , Phe ³⁶ ] PPY (25-36) RHFLNLVTRQRF (SEQ ID NO: 92) [Gln ²⁹ , Ile ³⁰ ] PYY (25-36) RHYLQIVTRQRY (SEQ ID NO: 93) [Gln ²⁹ , Val ³⁰ ] PYY (25-36) RHYLQVVTRQRY (SEQ ID NO: 94) [Gln ²⁹ , Ile ³¹ ] PYY (25-36) RHYLQLITRQRY (SEQ ID NO: 95) [Gln ²⁹ , Leu ³¹ ] PYY (25-36) RHYLQLLTRQRY (SEQ ID NO: 96) [Gln ²⁹ , Ser ³² ) PYY (25-36) RHYLQLVSRQRY (SEQ ID NO: 97) (Gln ²⁹ , Leu ³³ ] PYY (25-36) RHYLQLVTKQRY (SEQ ID NO: 98) [Gln ²⁹ , Asn ³⁴ ] PYY (25-36) RHYLQLVTRNRY (SEQ ID NO: 99) [Gln ²⁹ , Leu ³⁵ ] PYY (25-36) RHYLQLVTRQKY (SEQ ID NO: 100) [Gln ²⁹ , Thr ³⁶ ] PYY (25-36) RHYLQLVTRQRT (SEQ ID NO: 101) [Gln ²⁹ , Phe ³⁶ ] PYY (25-36) RHYLQLVTRQRF (SEQ ID NO: 102)

[Ile ³⁰ , Ile ³¹ ] PYY (25-36) RHYLNIITRQRY (SEQ ID NO: 103) [Ile ³⁰ , Leu ³¹ ] PYY (25-36) RHYLNILTRQRY (SEQ ID NO: 104) [Ile ³⁰ , Ser ³² ] PYY (25-36) RHYLNIVSRQRY (SEQ ID NO: 105) [Ile ³⁰ , Lys ³³ ] PYY (25-36) RHYLNIVTKQRY (SEQ ID NO: 106) [Ile ³⁰ , Asn ³⁴ ] PYY (25-36) RHYLNIVTRNRY (SEQ ID NO: 107) [Ile ³⁰ , Lys ³⁵ ] PYY (25-36) RHYLNIVTRQKY (SEQ ID NO: 108) [Ile ³⁰ , Thr ³⁶ ] PYY (25-36) RHYLNIVTRQRT (SEQ ID NO: 109) [Ile ³⁰ , Phe ³⁶ ] PYY (25-36) RHYLNIVTRQRF (SEQ ID NO: 110) [Val ³⁰ , Ile ³¹ ] PYY (25-36) RHYLNVITRQRY (SEQ ID NO: 111) [Val ³⁰ , Leu ³¹ ] PYY (25-36) RHYLNVLTRQRY (SEQ ID NO: 112) [Val ³⁰ , Ser ³² ] PYY (25-36) RHYLNVVSRQRY (SEQ ID NO: 113) [Val ³⁰ , Lys ³³ ] PYY (25-36) RHYLNVVTKQRY (SEQ ID NO: 114) [Val ³⁰ , Asn ³⁴ ] PYY (25-36) RHYLNVVTRNRY (SEQ ID NO: 115) [Val ³⁰ , Lys ³⁵ ] PYY (25-36) RHYLNVVTRQKY (SEQ ID NO: 116) (Val ³⁰ , Thr ³⁶ ] PYY (25-36) RHYLNVVTRQRT (SEQ ID NO: 117) [Val ³⁰ , Phe ³⁶ ] PYY (25-36) RHYLNWTRQRF (SEQ ID NO: 118) [Ile ³¹ , Ser ³² ] PYY (25-36) RHYLNLISRQRY (SEQ ID NO: 119) [Ile ³¹ , Lys ³³ ] PYY (25-36) RHYLNLITKQRY (SEQ ID NO: 120) [Ile ³¹ , Asn ³⁴ ] PYY (25-36) RHYLNLITRNRY (SEQ ID NO: 121) [Ile ³¹ , Lys ³⁵ ] PYY (25-36) RHYLNLITRQKY (SEQ ID NO: 122) [Ile ³¹ , Thr ³⁶ ] PYY (25-36) RHYLNLITRQRT (SEQ ID NO: 123) [Leu ³¹ , Phe ³⁶ ] PYY (25-36) RHYLNLITRQRF (SEQ ID NO: 124) [Leu ³¹ , Ser ³² ] PYY (25-36) RHYLNLLSRQRY (SEQ ID NO: 125) [Val ³¹ , Lys ³³ ] PYY (25-36) RHYLNLLTKQRY (SEQ ID NO: 126) [Leu ³¹ , Asn ³⁴ ] PYY (25-36) RHYLNLLTRNRY (SEQ ID NO: 127) [Leu ³¹ , Lys ³⁵ ] PYY (25-36) RHYLNLLTRQKY (SEQ ID NO: 128) [Leu ³¹ , Thr ³⁶ ] PYY (25-36) RHYLNLLTRQRT (SEQ ID NO: 129) (Leu ³¹ , Phe ³⁶ ] PYY (25-36) RHYLNLLTRQRF (SEQ ID NO: 130) [Ser ³² , Lys ³³ ] PYY (25-36) RHYLNLVSKQRY (SEQ ID NO: 131) [Ser ³² , Asn ³⁴ ] PYY (25-36) RHYLNLVSRNRY (SEQ ID NO: 132) [Ser ³² , Lys ³⁵ ] PYY (25-36) RHYLNLVSRQKY (SEQ ID NO: 133) (Ser ³² , Thr ³⁶ ] PYY (25-36) RHYLNLVSRQRT (SEQ ID NO: 134) [Ser ³² , Phe ³⁶ ] PYY (25-36) RHYLNLVSRQRY (SEQ ID NO: 135) [Lys ³³ , Asn ³⁴ ] PYY (25-36) RHYLNLVTKNRY (SEQ ID NO: 136) [Lys ³³ , Lys ³⁵ ] PYY (25-36) RHYLNLVTKQKY (SEQ ID NO: 137) [Lys ³³ , Thr ³⁶ ] PYY (25-36) RHYLNLVTKQRT (SEQ ID NO: 138) [Lys ³³ , Phe ³⁶ ] PYY (25-36) RHYLNLVTKQRF (SEQ ID NO: 139) [Asn ³⁴ , Lys ³⁵ ] PYY (25-36) RHYLNLVTRNKY (SEQ ID NO: 140) [Asn ³⁴ , Thr ³⁶ ] PYY (25-36) RHYLNLVTRNRT (SEQ ID NO: 141)

[Asn ³⁴ , Phe ³⁶ ] PYY (25-36) RHYLNLVTRNRF (SEQ ID NO: 142) [Lys ³⁵ , Thr ³⁶ ] PYY (25-36) RHYLNLVTRQKT (SEQ ID NO: 143) [Lys ³⁵ , Phe ³⁶ ] PYY (25-36) RHYLNLVTRQKF (SEQ ID NO: 144)

Point mutations PYY (24-36)

Peptide Sequence PYY (24-36) LRHYLNLVTRQRY (SEQ ID NO: 145) [Ile ²⁴ ] PYY (24-36) IRHYLNLVTRQRY (SEQ ID NO: 146) [Val ²⁴ ] PYY (24-36) VRHYLNLVTRQRY (SEQ ID NO: 147)

Variations of polypeptides (amino acid sequence variations) resulting from a combination of any of these three mutants with any of the above PYY mutants (25-36), for example, [Lys ²⁵ ] PPY (24-36), are also included as PYY mutations (24-36). ) (The sequence of amino acids = LKHYLNLVTRQRY (SEQ ID NO: 191)) is formed by combining mutations from SEQ ID NO: 36 with SEQ ID NO: 145.

Point mutations PYY (23-36)

Peptide Sequence PYY (23-36) SLRHYLNLVTRQRY (SEQ ID NO: 148) [Thr ²³ ] PYY (23-36) TLRHYLNLVTRQRY (SEQ ID NO: 149)

Variations of polypeptides (amino acid sequence variations) resulting from a combination of any of these two mutants with any of the above PYY mutants (25-36) and / or any of the above PYY mutants (24- 36), for example [Lys ²⁵ ] PPY (23-36) (Amino Acid Sequence = SLKHYLNLVTRQRY (SEQ ID NO: 192)) is formed by combining mutations from SEQ ID NO: 36 with SEQ ID NO: 148.

Point mutations PYY (22-36) 1

Peptide Sequence PYY (22-36) ASLRHYLNLVTRQRY (SEQ ID NO: 150) [Ser ²² ) PYY (22-36) SSLRHYLNLVTRQRY (SEQ ID NO: 151)

Variations of polypeptides (amino acid sequence variations) resulting from a combination of any of these two mutants with any of the above PYY mutants (25-36) and / or any of the above PYY mutants (23- 36), for example [Lys ²⁵ ] PPY (22-36) (Amino Acid Sequence = ASLKHYLNLVTRQRY (SEQ ID NO: 193)) is formed by combining mutations from SEQ ID NO: 36 with SEQ ID NO: 150.

Point mutations PYY (21-36)

Peptide Sequence PYY (21-36) YASLRHYLNLVTRQRY (SEQ ID NO: 152) [Thr ²¹ ] PYY (21-36) TASLRHYLNLVTRQRY (SEQ ID NO: 153) [Phe ²¹ ] PYY (21-36) FASLRHYLNLVTRQRY (SEQ ID NO: 154)

Variations of polypeptides (amino acid sequence variations) resulting from a combination of any of these three mutants with any of the above PYY mutants (25-36) and / or any of the above PYY mutants (22- 36), for example [Lys ²⁵ ] PPY (21-36) (Amino Acid Sequence = YASLKHYLNLVTRQRY (SEQ ID NO: 194)) is formed by combining mutations from SEQ ID NO: 36 with SEQ ID NO: 152.

Point mutations PYY (20-36)

Peptide Sequence PYY (20-36) YYASLRHYLNLVTRQRY (SEQ ID NO: 155) [Thr ²⁰ ] PYY (20-36) TYASLRHYLNLVTRQRY (SEQ ID NO: 156) [Phe20] PYY (20-36) FYASLRHYLNLVTRQRY (SEQ ID NO: 157)

Variations of polypeptides (amino acid sequence variations) resulting from a combination of any of these three mutants with any of the above PYY mutants (25-36) and / or any of the above PYY mutants (21- 36), for example [Lys ²⁵ ] PPY (20-36) (Amino Acid Sequence = YYASLKHYLNLVTRQRY (SEQ ID NO: 195)) is formed by combining mutations from SEQ ID NO: 36 with SEQ ID NO: 155.

Point mutations PYY (19-36)

Peptide Sequence PYY (19-36) RYYASLRHYLNLVTRQRY (SEQ ID NO: 158) [Lys ¹⁹ ] PYY (19-36) KYYASLRHYLNLVTRQRY (SEQ ID NO: 159)

Variations of polypeptides (amino acid sequence variations) resulting from a combination of any of these two mutants with any of the above PYY mutants (25-36) and / or any of the above PYY mutants (20- 36), for example [Lys ²⁵ ] PPY (19-36) (Amino acid sequence = RYYASLKHYLNLVTRQRY (SEQ ID NO: 196)) is formed by combining mutations from SEQ ID NO: 36 with SEQ ID NO: 158.

Point mutations PYY (18-36)]

Peptide Sequence PYY (18-36) NRYYASLRHYLNLVTRQRY (SEQ ID NO: 160) [Gln ¹⁸ ] PYY (18-36) QRYYASLRHYLNLVTRQRY (SEQ ID NO: 161)

Variations of polypeptides (amino acid sequence variations) resulting from the combination of any of these two mutants with any of the above PYY mutants (25-36) and / or any of the above PYY mutants (19- 36), for example [Lys ²⁵ ] PPY (18-36) (Amino Acid Sequence = NRYYASLKHYLNLVTRQRY (SEQ ID NO: 197)) is formed by combining mutations from SEQ ID NO: 36 with SEQ ID NO: 160.

PYY point mutations (17-36)

Peptide Sequence PYY (17-36) LNRYYASLRHYLNLVTRQRY (SEQ ID NO: 162) [Ile ¹⁷ ] PYY (17-36) INRYYASLRHYLNLVTRQRY (SEQ ID NO: 163) [VAL ¹⁷ ] PYY (17-36) VNRYYASLRHYLNLVTRQRY (SEQ ID NO: 164)

Variations of polypeptides (amino acid sequence variations) resulting from the combination of any of these three mutants with any of the above PYY mutants (25-36) and / or any of the above PYY mutants (18- 36), for example [Lys ²⁵ ] PPY (17-36) (Amino acid sequence = LNRYYASLKHYLNLVTRQRY (SEQ ID NO: 198)) is formed by combining mutations from SEQ ID NO: 36 with SEQ ID NO: 162.

Point mutations PYY (16-36)

Peptide Sequence PYY (16-36) ELNRYYASLRHYLNLVTRQRY (SEQ ID NO: 165) [Asp ¹⁶ ] PYY (16-36) DLNRYYASLRHYLNLVTRQRY (SEQ ID NO: 166)

Variations of polypeptides (amino acid sequence variations) resulting from a combination of any of these two mutants with any of the above PYY mutants (25-36) and / or any of the above PYY mutants (17- 36), for example [Lys ²⁵ ] PPY (16-36) (Amino Acid Sequence = ELNRYYASLKHYLNLVTRQRY (SEQ ID NO: 199)) is formed by combining mutations from SEQ ID NO: 36 with SEQ ID NO: 165.

Point mutations PYY (15-36)

Peptide Sequence PYY (15-36) EELNRYYASLRHYLNLVTRQRY (SEQ ID NO: 167) [Asp ¹⁵ ] PYY (15-36) DELNRYYASLRHYLNLVTRQRY (SEQ ID NO: 168)

Variations of polypeptides (amino acid sequence variations) resulting from a combination of any of these two mutants with any of the above PYY mutants (25-36) and / or any of the above PYY mutants (16- 36), for example [Lys ²⁵ ] PPY (15-36) (Amino Acid Sequence = EELNRYYASLKHYLNLVTRQRY (SEQ ID NO: 200)) is formed by combining mutations from SEQ ID NO: 36 with SEQ ID NO: 167.

Point mutations PYY (14-36)

Peptide Sequence PYY (14-36) PEELNRYYASLRHYLNLVTRQRY (SEQ ID NO: 169)

Variations of polypeptides (amino acid sequence variations) resulting from the combination of this mutant with any of the above PYY mutants (25-36) and / or any of the above PYY mutants (15-36) are also included as PYY mutations (14-36), for example [Lys ²⁵ ] PPY (14-36) (Amino Acid Sequence = PEELNRYYASLKHYLNLVTRQRY (SEQ ID NO: 201)) is formed by combining mutations from SEQ ID NO: 36 with SEQ ID NO: 169.

Point mutations PYY (13-36)

Peptide Sequence PYY (13-36) SPEELNRYYASLRHYLNLVTRQRY (SEQ ID NO: 170) [Thr ¹³ ] PYY (13-36) TPEELNRYYASLRHYLNLVTRQRY (SEQ ID NO: 171)

Variations of polypeptides (amino acid sequence variations) resulting from a combination of any of these two mutants with any of the above PYY mutants (25-36) and / or any of the above PYY mutants (14- 36), for example [Lys ²⁵ ] PPY (13-36) (Amino Acid Sequence = SEELNRYYASLKHYLNLVTRQRY (SEQ ID NO: 202)) is formed by combining mutations from SEQ ID NO: 36 with SEQ ID NO: 170.

Point mutations PYY (12-36)

Peptide Sequence PYY (12-36) ASPEELNRYYASLRHYLNLVTRQRY (SEQ ID NO: 172) [Ser ¹² ] PYY (12-36) SSPEELNRYYASLRHYLNLVTRQRY (SEQ ID NO: 173)

Variations of polypeptides (amino acid sequence variations) resulting from a combination of any of these two mutants with any of the above PYY mutants (25-36) and / or any of the above PYY mutants (13- 36), for example [Lys ²⁵ ] PPY (12-36) (Amino Acid Sequence = ASEELNRYYASLKHYLNLVTRQRY (SEQ ID NO: 203)) is formed by combining mutations from SEQ ID NO: 36 with SEQ ID NO: 172.

PYY point mutations (11-36)

Peptide Sequence PYY (11-36) DASPEELNRYYASLRHYLNLVTRQRY (SEQ ID NO: 174) [Glu ¹¹ ] PYY (11-36) EASPEELNRYYASLRHYLNLVTRQRY (SEQ ID NO: 175)

Variations of polypeptides (amino acid sequence variations) resulting from a combination of any of these two mutants with any of the above PYY mutants (25-36) and / or any of the above PYY mutants (12-36) are also included as PYY mutations (12-36). 36), for example [Lys ²⁵ ] PPY (11-36) (Amino Acid Sequence = DASEELNRYYASLKHYLNLVTRQRY (SEQ ID NO: 204)) is formed by combining mutations from SEQ ID NO: 36 with SEQ ID NO: 174.

Point mutations PYY (10-36)

Peptide Sequence PYY (10-36) EDASPEELNRYYASLRHYLNLVTRQRY (SEQ ID NO: 176) [ASP ¹⁰ ] PYY (10-36) DDASPEELNRYYASLRHYLNLVTRQRY (SEQ ID NO: 177)

Variations of polypeptides (amino acid sequence variations) resulting from a combination of any of these two mutants with any of the above PYY mutants (25-36) and / or any of the above PYY mutants (11- 36), for example [Lys ²⁵ ] PPY (10-36) (Amino-kilot sequence = EDASEELNRYYASLKHYLNLVTRQRY (SEQ ID NO: 205)) is formed by combining mutations from SEQ ID NO: 36 with SEQ ID NO: 176.

Point mutations PYY (9-36)

Peptide Sequence PYY (9-36) GEDASPEELNRYYASLRHYLNLVTRQRY (SEQ ID NO: 178)

Variations of polypeptides (amino acid sequence variations) resulting from the combination of this mutant with any of the above PYY mutants (25-36) and / or any of the above PYY mutants (10-36) are also included as PYY mutations (9-36), for example [Lys ²⁵ ] PPY (9-36) (Amino Acid Sequence = GEDASEELNRYYASLKHYLNLVTRQRY (SEQ ID NO: 206)) is formed by combining mutations from SEQ ID NO: 36 with SEQ ID NO: 178.

Point mutations PYY (8-36)

Peptide Sequence PYY (8-36) PGEDASPEELNRYYASLRHYLNLVTRQRY (SEQ ID NO: 179)

Variations of polypeptides (amino acid sequence variations) resulting from the combination of this mutant with any of the above PYY mutants (25-36) and / or any of the above PYY mutants (9-36) are also included as PYY mutations (8-36), for example [Lys ²⁵ ] PPY (8-36) (Amino Acid Sequence = SEQ ID NO: 207)) is formed by combining mutations from SEQ ID NO: 36 with SEQ ID NO: 179.

Point mutations PYY (7-36)

Peptide Sequence PYY (7-36) APGEDASPEELNRYYASLRHYLNLVTRQRY (SEQ ID NO: 180) [Ser ⁹ ] PYY (7-36) SPGEDASPEELNRYYASLRHYLNLVTRQRY (SEQ ID NO: 181)

Variations of polypeptides (amino acid sequence variations) resulting from a combination of any of these two mutants with any of the above PYY mutants (25-36) and / or any of the above PYY mutants (8- 36), for example [Lys ²⁵ ] PPY (7-36) (Amino Acid Sequence = APGEDASEELNRYYASLKHYLNLVTRQRY (SEQ ID NO: 208)) is formed by combining mutations from SEQ ID NO: 36 with SEQ ID NO: 180.

Point mutations PYY (6-36)

Peptide Sequence PYY (6-36) EAPGEDASPEELNRYYASLRHYLNLVTRQRY (SEQ ID NO: 182) [Asp ⁶ ] PYY (6-36) DAPGEDASPEELNRYYASLRHYLNLVTRQRY (SEQ ID NO: 183)

Variations of polypeptides (amino acid sequence variations) resulting from a combination of any of these two mutants with any of the above PYY mutants (25-36) and / or any of the above PYY mutants (7- 36), for example [Lys ²⁵ ] PPY (6-36) (Amino acid sequence = EAPGEDASEELNRYYASLKHYLNLVTRQRY (SEQ ID NO: 209)) is formed by combining mutations from SEQ ID NO: 36 with SEQ ID NO: 182.

Point mutations PYY (5-36)

Peptide Sequence PYY (5-36) PEAPGEDASPEELNRYYASLRHYLNLVTRQRY (SEQ ID NO: 184)

Variations of polypeptides (amino acid sequence variations) resulting from the combination of this mutant with any of the above PYY mutants (25-36) and / or any of the above PYY mutants (6-36) are also included as PYY mutations (5-36), for example [Lys ²⁵ ] PPY (5-36) (Amino Acid Sequence = PEAPGEDASPEELNRYYASLKHYLNLVTRQRY SEQ ID NO: 210)) is formed by combining mutations from SEQ ID NO: 36 with SEQ ID NO: 184.

Point mutations PYY (4-36)

Peptide Sequence PYY (4-26) KPEAPGEDASPEELNRYYASLRHYLNLVTRQRY (SEQ ID NO: 185) [Arg ⁴ ] PYY (4-36) RPEAPGEDASPEELNRYYASLRHYLNLVTRQRY (SEQ ID NO: 186) [Gln ⁴ ] PYY (4-36) QPEAPGEDASPEELNRYYASLRHYLNLVTRQRY (SEQ ID NO: 187) [Asn ⁴ ] PYY (4-36) NPEAPGEDASPEELNRYYASLRHYLNLVTRQRY (SEQ ID NO: 188)

Variations of polypeptides (amino acid sequence variations) resulting from a combination of any of these four mutants with any of the above PYY mutants (25-36) and / or any of the above PYY mutants (5- 36), for example [Lys ²⁵ ] PPY (4-36) (Amino acid sequence = KPEAPGEDASEELNRYYASLKHYLNLVTRQRY (SEQ ID NO: 211)) is formed by combining mutations from SEQ ID NO: 36 with SEQ ID NO: 185.

Point mutations PYY (3-36)

Peptide Sequence PYY (3-36) IKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY (SEQ ID NO: 1) [Leu ³ ] PYY (3-36) LKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY (SEQ ID NO: 189) [Va ¹³ ] PYY (3-36) VKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY] (SEQ ID NO: 190)

Variations of polypeptides (amino acid sequence variations) resulting from a combination of any of these three mutants with any of the above PYY mutants (25-36) and / or any of the above PYY mutants (4- 36), for example [Lys ²⁵ ] PPY (3-36) (Amino Acid Sequence = IKPEAPGEDASEELNRYYASLKHYLNLVTRQRY (SEQ ID NO: 212)) is formed by combining mutations from SEQ ID NO: 36 with SEQ ID NO: 1.

PYY agonists (NPY analogs) having the formula: XQR ₁₉ -R ₂₀ -R ₂₁ -R ₂₂ -R ₂₃ -Leu-R ₂₅ -R ₂₆ -R ₂₇ -R ₂₈ -R ₂₉ -R ₃₀ -R ₃₁ - R ₃₂ —Arg — R ₃₄ —Arg — R36-Y, wherein X is H or C ^a Me or N ^a Me or a deamino or acyl group containing 7 or less carbon atoms; Q is represented by R ₁₇ -R ₁₈ , R ₁₈ or desQ; R ₁₇ is Met, Arg, Nle, Nva, Leu, Ala or D-Ala; R ₁₈ is Ala, Ser, Ile, D-Ala, D-Ser or D-Ile; R ₁₉ is Arg, Lys or Gln; R ₂₀ is Tyr or Phe; R ₂₁ is Tyr, Glu, His or Ala; R ₂₂ is Ser, Ala, Thr, Asn or Asp; R ₂₃ is Ala, Asp, Glu, Gln Asn or Ser; R ₂₅ is Arg or Gln; R ₂₆ is represented by His, Arg or Gln; R ₂₇ is represented by Phe or Tyr; R ₂₈ is Ile, Leu, Val or Arg; R ₂₉ is represented by Asn or Ile; R ₃₀ is represented by Leu, Met, Thr or Val; R ₃₁ is Ile, Val or Leu; R ₃₂ is represented by Thr or Phe; R ₃₄ is Gln, Pro or His; R ₃₆ is Phe or Tyr and Y is NH ₂ or OH; provided that when Q is R ₁₈ , at least one of R ₂₇ and R ₃₆ is Phe. NPY analogs have the following uses: as potent postsynaptic agents for the treatment of hypertension and cardiogenic shock, as well as for the treatment of acute cardiovascular circulatory failure and increased intracellular calcium content. See U.S. Patent No. 5026685.

Some preferred NPY analogs have the formula: XR ₁₈ -Arg-Tyr-Tyr-R ₂₂ -R ₂₃ -Leu-Arg-nis-Tyr-R ₂₈ -Asn-Leu-R ₃₁ -Thr-Arg-Gln-Arg-Tyr- NH ₂ , in which X is H or C ^a Me or N ^a Me or a deamino or acyl group containing 7 carbon atoms or less; R ₁₈ is Ala or Ser; R ₂₂ is Ser or Ala; R ₂₃ is Ala or Ser; R ₂₇ is represented by Phe or Tyr; R ₂₈ is represented by Ilé or Leu; R ₃₁ is Il or Val and R ₃₆ is Phe or Tyr provided that at least one of R ₂₇ and R ₃₆ is Phe. See U.S. Patent No. 5026685.

Other contemplated NPY analogues have the formula:

XR ₁₇ -R ₁₈ -Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-R ₂₇ -Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-R ₃₆ -NH ₂ , in which R ₁₇ represents Arg or Leu and R ₁₈ represents Ser or Ala or Ilé and in which X, R ₂₇ and R ₃₆ are indicated above.

Another preferred analogs of NPY have the formula:

XR ₁₈ -Arg-Tyr-Tyr-Ala-Ser-Leu-R ₂₅ -His-R ₂₇ -Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-R ₃₆ -NH ₂ , in which X is a deamino group or C ^a Me or N ^a Me and where R ₁₈ , R ₂₅ , R ₂₇ and R ₃₆ are as defined above.

Examples of these NPY agonists include:

pNPY (17-36) having the formula:

H-Leu-Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 217 )

The hNPY peptide (17-36) having the formula:

H-Met-Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 218 )

The peptide [Phe ²⁷ ] -NPY (18-36) having the formula:

H-Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Phe-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 219)

The peptide [Ac-D-Ala ¹⁷ ] -NPY (17-36) having the formula:

Ac-D-Ala-Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO : 220)

The NPY peptide (19-36) having the formula:

H-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 221)

The peptide [Nle ¹⁷ ] -NPY (17-36) having the formula:

H-Nle-Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 222 )

The peptide [D-Ser ¹⁸ ] -NPY (18-36) having the formula:

HD-Ser-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 223)

The peptide [Ala ¹⁷ , His ²¹ ] -NPY (17-36) having the formula:

H-Ala-Ala-Arg-Tyr-His-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 224 )

The peptide [D-Ile ₁₈ ] -NPY (18-36) having the formula:

D-Ile-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 225)

The peptide [Ac-Arg ¹⁷ ] -NPY (17-36) having the formula:

Ac-Arg-Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 226 )

The peptide [Gln ¹⁹ ] -NPY (19-36) having the formula:

H-Gln-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 227)

The peptide [Phe ²⁰ ] -NPY (18-36) having the formula:

H-Ala-Arg-Phe-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 228)

The peptide [C ^a MeLeu ¹⁷ ] -pNPY (17-36)) having the formula:

HC ^a MeLeu-Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 229 )

The peptide [N ^a MeLeu ¹⁷ ] -pNPY (17-36) having the formula:

HN ^a MeLeu-Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 230 )

The peptide [desamino Ala ¹⁸ ] -NpY (18-36) having the formula:

desamino-Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 231)

The peptide [For-Ala ¹⁸ , Glu ²³ , Arg ²⁶ ] -NPY (18-36) having the formula:

For-Ala-Arg-Tyr-Tyr-Ser-Glu-Leu-Arg-Arg-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 232)

The peptide [Nva ¹⁸ , Ala ²¹ , Leu ²⁸ ] -NPY (17-36) having the formula:

H-Nva-Ala-Arg-Tyr-Ala-Ser-Ala-Leu-Arg-His-Tyr-Leu-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 233 )

The peptide [Thr ²² , Gln ²³ ] -NPY (18-36)) having the formula:

H-Ala-Arg-Tyr-Tyr-Thr-Gln-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 234)

The peptide [desamino Leu ¹⁷ , Asn ²³ , Val ³⁰ ] -NPY (17-36)) having the formula:

H-Desamino Leu-Ala-Arg-Tyr-Tyr-Ser-Asn-Leu-Arg-His-Tyr-Ile-Asn-VAL-Ile-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 235)

The peptide [Asp ²² , Ser ²³ , Thr ³⁰ ] -NPY (18-36) having the formula:

H-Ala-Arg-Tyr-Tyr-Asp-Ser-Leu-Arg-His-Tyr-Ile-Asn-Thr-Ile-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 236)

The peptide [Gln ²⁵ , Leu ³¹ , Pro ³⁴ ] -NPY (18-36)) having the formula:

H-Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Gln-His-Tyr-Ile-Asn-Leu-Leu-Thr-Arg-Pro-Arg-Tyr-NH ₂ (SEQ ID NO: 237)

The peptide [Gln ²⁵ , Phe ³⁶ ] -NPY (17-36) having the formula:

H-Leu-Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-Gln-Tyr-Arg-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Phe-NH ₂ (SEQ ID NO: 238 )

The peptide [Phe ³⁶ ] -pPYY (19-36) having the formula:

H-Arg-Tyr-Tyr-Ala-Ser-Leu-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Phe-NH ₂ (SEQ ID NO: 239)

The peptide pPYY (18-36)) having the formula:

H-Ser-Arg-Tyr-Tyr-Ala-Ser-Leu-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 240)

The peptide [Ac-Ser ¹⁸ , Phe ²⁷ ] -pYY (18-36) having the formula:

Ac-Ser-Arg-Tyr-Tyr-Ala-Ser-Leu-Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 241)

The peptide [Nle ¹⁷ , Asn ²² , Phe ²⁷ ] -NPY (17-36) having the formula:

H-Nle-Ala-Arg-Tyr-Tyr-Asn-Ala-Leu-Arg-His-Phe-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 242 )

The peptide [D-Ala ¹⁸ , Glu ²¹ , His ³⁴ ] -NPY (18-36)) having the formula:

HD-Ala-Arg-Tyr-GLU-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-His-Arg-Tyr-NH ₂ (SEQ ID NO: 243)

The peptide [Bz-Leu ¹⁷ , Pro ³⁴ , Phe ³⁶ ] -pNPY (17-36)) having the formula:

Bz-Leu-Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Pro-Arg-Phe-NH ₂ (SEQ ID NO: 244 )

The peptide [Lys ¹⁹ , Phe ²⁷ , Val ²⁸ ] -NPY (18-36)) having the formula:

H-Ala-Lys-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Phe-Val-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 245)

The peptide [D-Ala, Val ²⁸ , Phe ³² ] -NPY (17-36)) having the formula:

D-Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Val-Asn-Leu-Ile-Phe-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 246)

The peptide [C ^a MeSer ¹⁸ , Met ³⁰ , Phe ³⁶ ] -NPY (18-36)) having the formula:

HC ^a MeSer-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Met-Ile-Thr-Arg-Gln-Arg-Phe-NH ₂ (SEQ ID NO: 247)

The peptide [Arg ¹⁷ , Ile ¹⁸ , Phe ^27.36 ] -NPY (17-36) having the formula:

H-Arg-Ile-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Phe-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Phe-NH ₂ (SEQ ID NO: 248 )

The peptide [Ser ¹⁸ , Phe ²⁷ ] -pNPY (17-36) having the formula:

H-Leu-Ser-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Phe-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 249 )

The peptide [N ^a Melle ¹⁸ , Gln ²⁵ , Phe ²⁷ ] -NPY (18-36) having the formula:

N ^a Melle-Arg-Tyr-Tyr-Ser-Ala-Leu-Gln-His-Phe-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 250)

The peptide [D-Ser ¹⁸ , Phe ³⁶ ] -NPY (18-36) having the formula:

HD-Ser-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Phe-NH ₂ (SEQ ID NO: 251)

The peptide [Asp ²³ , Arg ²⁶ ] hNPY (17-36) having the formula:

H-Met-Ala-Arg-Tyr-Tyr-Ser-Asp-Leu-Arg-Arg-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 252 )

The peptide [Glu ²³ , Ile ²⁹ ] -NPY (18-36) having the formula:

H-Ala-Arg-Tyr-Tyr-Ser-Glu-Leu-Arg-His-Tyr-Ile-Ile-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 253)

The peptide [D-Ala ¹⁷ ] -NPY (17-36) -OH having the formula:

D-Ala-Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-OH (SEQ ID NO: 254) .

Other YY peptide agonists have the formula:

wherein:

X is a chain of 0-5 amino acids, including a chain in which the N-terminal amino acid is linked to R ₁ and R ₂

Y is a chain of 0-4 amino acids, including a chain in which the C-terminal amino acid is linked to R ₃ and R ₄ ,

R ₁ is H, C ₁ -C ₂ alkyl (e.g. methyl), C ₆ -C ₁₈ aryl (e.g. phenyl, naphthylacetyl), C ₁ -C ₁₂ acyl (e.g. formyl, acetyl and myristoyl), C ₇ -C ₁₈ aralkyl (e.g. benzyl) or C ₇ -C ₁₈ alkaryl (e.g. p-methylphenyl);

R ₂ is H, C ₁ -C ₁₂ alkyl (e.g. methyl), C ₆ -C ₁₈ aryl (e.g. phenyl, naphthylacetyl), C ₁ -C ₁₂ acyl (e.g. formyl, acetyl and myristoyl), C ₇ -C ₁₈ aralkyl (e.g. benzyl) or C ₇ -C ₁₈ alkaryl (e.g. p-methylphenyl);

A ²² is an aromatic amino acid, Ala, Aib, Anb, N-Me-Ala or a deletion;

A ²³ is Ser, Thr, Ala, N-Me-Ser, N-Me-Thr, N-Me-Ala or a deletion;

A ²⁴ - Leu, Ile, Vat, Trp, Gly, Aib, Anb, N-Me-Leu or a deletion;

A ²⁵ is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-∈-NH-R (where R is H, a C ₁ -C ₁₀ branched or straight chain alkyl group or an aryl group), Orn or deletion;

A ²⁶ - His, Thr, 3-Me-His, 1-Me-His, β-pyrozolylamine, N-Me-His, Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-∈-NH-R (where R is H, a C ₁ -C ₁₀ branched or straight chain alkyl group or an aryl group), Orn or a deletion;

A ²⁷ is an aromatic amino acid other than Tyr;

A ²⁸ - Leu, Ile, Vat, Trp, Aib, Aib, Anb or N-Me-Leu;

A ²⁹ - Asn, Ala, Gln, Gly, Trp, or N-Me-Asn;

A ³⁰ - Leu, Ile, Val, Trp, Aib, Anb or N-Me-Leu;

A ³¹ is Vat, He, Trp, Aib, Anb, or N-Me-Val;

A ³² is Thr, Ser, N-Me-Set, or N-Me-Thr;

R ₃ is H, C ₁ -C ₁₂ alkyl (e.g. methyl), C ₆ -C ₁₈ aryl (e.g. phenyl, naphthylacetyl), C ₁ -C ₁₂ acyl (e.g. formyl, acetyl and myristoyl), C ₇ -C ₁₈ aralkyl (e.g. benzyl) or C ₇ -C ₁₈ alkaryl (e.g. p-methylphenyl);

R ₄ is H, C ₁ -C ₁₂ alkyl (e.g. methyl), C ₆ -C ₁₈ aryl (e.g. phenyl, naphthylacetyl), C ₁ -C ₁₂ acyl (e.g. formyl, acetyl and myristoyl), C ₇ -C ₁₈ aralkyl (e.g. benzyl) or C ₇ -C ₁₈ alkaryl (e.g. p-methylphenyl) or a pharmaceutically acceptable salt thereof. See U.S. Patent No. 5574010.

Particularly preferred agonists of this formula suitable for use in the method corresponding to the description of the invention include:

N-α-Ala-Ser-Leu-Arg-His-Trp-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ ID NO: 255).

Other YY peptide agonists have the formula:

wherein:

The N-terminal amino acid is linked to R ₁ and R ₂ ;

Y is a chain of 0-4 amino acids, including a chain, the C-terminal amino acid of which is linked to R ₃ and R ₄ ;

R ₁ is H, C ₁ -C ₁₂ alkyl, C ₆ -C ₁₈ aryl, C ₁ -C ₁₂ acyl, C ₇ -C ₁₈ aralkyl or C ₇ -C ₁₈ alkaryl;

R ₂ is H, C ₁ -C ₁₂ alkyl, C ₆ -C ₁₈ aryl, C ₁ -C ₁₂ acyl, C ₇ -C ₁₈ aralkyl or C ₇ -C ₁₈ alkaryl;

A ²⁵ is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-∈-NH-R (where R is H, a C ₁ -C ₁₀ branched or straight chain alkyl group or an aryl group), Orn or deletion;

A ²⁶ - Ala, His, Thr, 3-Me-His, 1-Me-His, β-pyrozolylalanine, N-Me-His, Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-∈-NH —R (where R is H, a C ₁ -C ₁₀ branched or straight chain alkyl group or an aryl group), Orn or a deletion;

A ²⁷ is an aromatic amino acid;

A ²⁸ - Leu, Ile, Val, Trp, Aib, Anb or N-Me-Leu;

A ²⁹ - Asn, Ala, Gln, Gly, Trp, or N-Me-Asn;

A ³⁰ - Leu, Ile, Val, Trp, Aib, Anb or N-Me-Leu;

A ³¹ - Val, Ile, Trp, Aib, Anb or N-Me-Val;

A ³² is Thr, Set, N-Me-Set or N-Me-Thr or D-Trp;

R ₃ is H, C ₁ -C ₁₂ alkyl, C ₆ -C ₁₈ aryl, C ₁ -C ₁₂ acyl C ₇ -C ₁₈ aralkyl or C ₇ -C ₁₈ alkaryl and

R ₄ is H, C ₁ -C ₁₂ alkyl, C ₆ -C ₈ aryl, C ₁ -C ₁₂ acyl C ₇ -C ₁₈ alkaryl or C ₇ -C ₁₈ alkaryl or a pharmaceutically acceptable salt thereof. Note that, unless otherwise indicated, for all YY peptide agonists described in this context, each amino acid residue, for example, Leu and A1, represents the structure NH - C (R) H-CO--, where R is the side chain. The lines between amino acid residues represent peptide bonds that connect amino acids. In addition, if the amino acid residue is optically active, it is present in the L-shape configuration, which is implied unless the D-form is specifically designated.

Other PYY agonists have the formula:

wherein:

X is a chain of 0-5 amino acids, including a chain in which the N-terminal amino acid is linked to R ₁ and R ₂ ;

Y is a chain of 0-4 amino acids, including a chain in which the C-terminal amino acid is linked to R ₃ and R ₄ ;

R ₁ is H, C ₁ -C ₁₂ alkyl (e.g. methyl), C ₆ -C ₁₈ aryl (e.g. phenyl, naphthylacetyl), C ₁ -C ₁₂ acyl (e.g. formyl, acetyl and myristoyl), C ₇ -C ₁₈ aralkyl (e.g. benzyl) or C ₇ -C ₁₈ alkaryl (e.g. p-methylphenyl);

R ₂ is H, C ₁ -C ₁₂ alkyl (e.g. methyl), C ₆ -C ₁₈ aryl (e.g. phenyl, naphthylacetyl), C ₁ -C ₁₂ acyl (e.g. formyl, acetyl and myristoyl), C ₇ -C ₁₈ aralkyl (e.g. benzyl) or C ₇ -C ₁₈ alkaryl (e.g. p-methylphenyl);

A ²² is an aromatic amino acid, Ala, Aib, Anb, N-Me-Ala or a deletion;

A ²³ is Ser, Thr, Ala, Aib, N-Me-Ser, N-Me-Thr, N-Me-Ala or a deletion;

A ²⁴ - Leu, Ile, Val, Trp, Gly, Nle, Nva, Aib, Anb, N-Me-Leu or a deletion;

A ²⁵ is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lye-∈-NH-R (where R is H, a C ₁ -C ₁₀ -branched or unbranched alkyl group or an aryl group), Orn or deletion;

A ²⁶ - Ala, His, Thr, 3-Me-His, 1-Me-His, β-pyrozoyalanine, N-Me-His, Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-∈-NH —R (where R is H, a C ₁ -C ₁₀ branched or unbranched alkyl group or an aryl group), Orn or a deletion;

A ²⁷ is an aromatic amino acid other than Tyr;

A ²⁸ - Leu, Ile, Val, Trp, Nle, Nva, Aib, Anb or N-Me-Leu;

A ²⁹ - Asn, Ala, Gln, Gly, Trp or N-Me-Asn;

A ³⁰ - Leu, Ile, Val, Trp, Nle, Nva, Aib, Anb or N-Me-Leu;

A ³¹ - Val, Leu, Ile, Trp, Nle, Nva, Aib, Anb or N-Me-Val;

A ³² is Thr, Ser, N-Me-Ser, N-Me-Thr or D-Trp;

R ₃ is H, C ₁ -C ₁₂ alkyl (e.g. methyl), C ₆ -C ₁₈ aryl (e.g. phenyl, naphthylacetyl), C ₁ -C ₁₂ acyl (e.g. formyl, acetyl and myristoyl), C ₇ -C ₁₈ aralkyl (e.g. benzyl) or C ₇ -C ₁₈ alkaryl (e.g. p-methylphenyl) and

R4 is H, C ₁ -C ₁₂ alkyl (e.g. methyl), C ₆ -C ₁₈ aryl (e.g. phenyl, naphthylacetyl), C ₁ -C ₁₂ acyl (e.g. formyl, acetyl and myristoyl), C ₇ -C ₁₈ aralkyl (e.g. benzyl) or C ₇ -C ₁₈ alkaryl (e.g. p-methylphenyl) or a pharmaceutically acceptable salt thereof.

In preferred embodiments, A ²⁷ is Phe, Nal, Bip, Pep, Tic, Trp, Bth, Thi, or Dip.

In preferred embodiments, the implementation of X-A ¹⁷ -A ¹⁸ -A ¹⁹ -A ²⁰ -A ²¹ , where

A ¹⁷ - Cys, Leu, Ile, Val, Nle, Nva, Aib, Anb or N-Me-Leu;

A ¹⁸ is Cys, Ser, Thr, N-Me-Ser or N-Me-Thr;

A ¹⁹ is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-∈-NH-R (where R is H, a C ₁ -C ₁₀ -branched or unbranched alkyl group, or C ₆ -C ₁₈ - aryl group), Cys or Orn;

A ²⁰ is an aromatic amino acid or Cys and

A ²¹ is an aromatic amino acid, Cys or a pharmaceutically acceptable salt thereof. In still other preferred embodiments, YA ³³ -A ³⁴ -A ³⁵ -A ³⁶ , wherein

A ³³ is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-∈-NH-R (where R is H, a C ₁ -C ₁₀ -branched or unbranched alkyl group, or C ₆ -C ₁₈ - aryl group), Cys or Orn;

A ³⁴ Cys, Gln Asn, Ala, Gly, N-Me-C1n, Aib or Anb;

A ³⁵ is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-∈-NH-R (where R is H, a C ₁ -C _{10 is a} branched or unbranched alkyl group, or C ₆ -C ₁₈ is aryl group), Cys or Orn and

A ³⁶ is an aromatic amino acid, Cys, or a pharmaceutically acceptable salt thereof. See U.S. Patent No. 5604203.

A particular embodiment includes compounds having the formula:

N-α-Ac-Ala-Ser-Leu-Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ. ID. NO: 325),

H-Ala-Ser-Leu-Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ. ID. NO: 326), N-α-Ac- Ala-Ser-Leu-Arg-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ. ID. NO: 327), N-α-Ac-Ala-Ser-Leu-Arg-His-THI-Leu- Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ. ID. NO: 328),

N-α-Ac-Tyr-Ser-Leu-Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ. ID. NO: 329) or their pharmaceutically acceptable salt.

Other PYY agonists have the formula:

in which the N-terminal amino acid is linked to R ₁ and R ₂ ; Y is a chain of 0-4 amino acids, including a chain in which the C-terminal amino acid is linked to R ₃ and R ₄ ;

R ₁ is H, C ₁ -C ₁₂ alkyl (e.g. methyl), C ₆ -C ₁₈ aryl (e.g. phenyl, naphthylacetyl), C ₁ -C ₁₂ acyl (e.g. formyl, acetyl and myristoyl), C ₇ -C ₁₈ aralkyl (e.g. benzyl) or C ₇ -C ₁₈ alkaryl (e.g. p-methylphenyl);

R ₂ is H, C ₁ -C ₁₂ alkyl (e.g. methyl), C ₆ -C ₁₈ aryl (e.g. phenyl, naphthylacetyl), C ₁ -C ₁₂ acyl (e.g. formyl, acetyl and myristoyl), C ₇ -C ₁₈ aralkyl (e.g. benzyl) or C ₇ -C ₁₈ alkaryl (e.g. p-methylphenyl);

A ²⁵ is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-∈-NH-R (where R is H, a C ₁ -C ₁₀ -alkyl group with a branched or unbranched chain, or C ₆ -C ₁₈ - aryl group), Orn or deletion;

A ²⁶ -Ala, His, Thr, 3-Me-His, 1-Me-His, β-pyrozolylalanine, N-Me-His, Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-∈-NH —R (where R is H, a C ₁ -C ₁₀ branched or unbranched alkyl group, or a C ₆ -C ₁₈ aryl group), Orn or a deletion;

A ²⁷ is an aromatic amino acid;

A ²⁸ - Leu, Ile, Val, Trp, Nle, Nva, Aib, Anb or N-Me-Leu;

A ²⁹ - Asn, Ala, Gln, Gly, Trp or N-Me-Asn;

A ³⁰ - Leu, Ile, Val, Trp, Nle, Nva, Aib, Anb or N-Me-Leu;

A ³¹ - Val, Ile, Trp, Nle, Nva, Aib, Anb or N-Me-Val;

A ³² is Thr, Ser, N-Me-Ser, N-Me-Thr or D-Trp;

R ₃ is H, C ₁ -C ₁₂ alkyl (e.g. methyl), C ₆ -C ₁₈ aryl (e.g. phenyl, naphthylacetyl), C ₁ -C ₁₂ acyl (e.g. formyl, acetyl and myristoyl), C ₇ -C ₁₈ aralkyl (e.g. benzyl) or C ₇ -C ₁₈ alkaryl (e.g. p-methylphenyl) and

R ₄ is H, C ₁ -C ₁₂ alkyl (e.g. methyl), C ₆ -C ₁₈ aryl (e.g. phenyl, naphthylacetyl), C ₁ -C ₁₂ acyl (e.g. formyl, acetyl and myristoyl), C ₇ -C ₁₈ aralkyl (e.g. benzyl) or C ₇ -C ₁₈ alkaryl (e.g. p-methylphenyl) or a pharmaceutically acceptable salt thereof. See U.S. Patent No. 5604203.

In specific embodiments, A ²⁷ is Phe, Nal, Bip, Pcp, Tic, Trp, Bth, Thi, or Dip.

In specific embodiments, implementation of X-A ³³ -A ³⁴ -A ³⁵ -A ³⁶ , where

A ³³ is Arg, Lys, homo-Arg, diethyl-homo-Arg, [Lys-∈-NH-R] (where R is H, a C ₁ -C ₁₀ -branched or unbranched alkyl group, or C ₆ -C ₁₈ aryl group), Cys or Orn;

A ³⁴ Gln, Asn, Ala, Gly, N-Me-Gln, Aib, Cys or Anb;

A ³⁵ is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-∈-NH-R (where R is H, a C ₁ -C ₁₀ -branched or unbranched alkyl group, or C ₆ -C ₁₈ - aryl group), Cys or Orn and

A ³⁶ is an aromatic amino acid, Cys, or a pharmaceutically acceptable salt thereof.

Preferably, when the compound has the formula:

N-α-Ac-Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH ₂ (SEQ. ID. NO: 324).

Examples of PYY agonists include:

YPAKEAPGEDASPEELSTYYASLR [im-DNP-His ²⁶ ] (SEQ ID NO: 256) YLNLVTRZRY-NH ₂ PYY (22-36) ASLRHYLNLVTRQRY-NH ₂ (SEQ ID NO: 257) [Ala ³² ] PYY ASLRHYLNLV [Ala] RQRY-NH ₂ (SEQ ID NO: 258) [Ala ^23.32 ] PYY A [Ala] LRHYLNLV [Ala] RQRY-NN ₂ (SEQ ID NO: 259) [Glu ²⁸ ] PYY (22-36) ASLRHY [Glu] NLVTRQRY-NH ₂ (SEQ ID NO: 260) N-α-Ac-PYY (22-36) N-α-Ac-ASLRHYLNLVTRORY-NH ₂ (SEQ ID NO: 261) N-α-Ac [p.CL.Phe ²⁶ ] PYY N-α-Ac-ASLR [p.CL.Phe ²⁶ ] YLNLVTRQRY-NH ₂ (SEQ ID NO: 262) N-α-Ac [Glu ₂₈ ] PYY N-α-Ac-ASLRHY [Glu] NLVTRQRY-NH ₂ (SEQ ID NO: 263) N-α-Ac [Phe ²⁷ ] PYY N-α-Ac-ASLRH [Phe] ENLVTRQR [N-Me-Tyr] -NH ₂ (SEQ ID NO: 264) N-α-Ac] 8N-Me-Tyr ³⁶ ] PYY N-α-Ac-ASLRHYENLVTROR [N-Me-Tyr] -NH ₂ (SEQ ID NO: 265) N-α-Maristoyl-PYY (2214 36) N-α-myristoyl-ASLRHYLNLVTRQRY-NH ₂ (SEQ ID NO: 266) N-α-naphthylacetyl-PYY (22-36) N-α-naphthylacetyl-ASLRHYLNLVTRQRY-NH ₂ (SEQ ID NO: 267) N-α-Ac [Phe ²⁷ ] PYY N-α-Ac-ASLRH [Phe] ENLVTROR [N-Me-Tyr] -NH ₂ (SEQ ID NO: 268) N-α-Ac-PYY (22-36) N-α-Ac-ASLRHYLNLVTRQRY-NH ₂ (SEQ ID NO: 269) N-α-Ac- [Bth ²⁷ ] PYY (22-36) N-α-Ac-ASLRH [Bth] LNLVTRQRY-NH ₂ (SEQ ID NO: 270) N-α-Ac- [Bip ²⁷ ] PYY (22-36) (SEQ ID NO: 271) N-α-Ac-ASLRH [Bth] LNLVTRQRY-NH ₂ (SEQ ID NO: 272) N-α-Ac- [Nal ²⁷ ] PYY (22-36)

N-α-Ac-ASLRH [Bth] LNLVTRQRY-NH ₂ (SEQ ID NO: 273) N-α-Ac- [Trp ²⁷ ] PYY (22-36) (SEQ ID NO: 274) N-α-Ac-ASLRH [Trp] LNLVTRQRY-NH ₂ (SEQ ID NO: 275) N-α-Ac- [Thi ²⁷ ] PYY (22-36) N-α-Ac-ASLRN [Thi] LNLVTRQRY-NH ₂ (SEQ ID NO: 276) N-α-Ac- [Tic ²⁷ ] PYY (22-36) N-α-Ac-ASLRH [Tic] LNLVTRQRY-NH ₂ (SEQ ID NO: 277) N-α-Ac- [Phe ²⁷ ] PYY (25-36) N-α-Ac-H [Phe] LNLVTRQRY-NH ₂ (SEQ ID NO: 279) N-α-Ac- [Phe ²⁷ , Thi ²⁷ ] PYY (22-36) N-α-Ac-ASLRH [Phe] LNLVTRQR (Thi] -NH ₂ (SEQ ID NO: 280) N-α-Ac- [Thz ²⁶ , Phe ²⁷ ] PYY (22-36) N-α-Ac-ASLRH [Thz] [Phe] LNLVTRQRY-NH ₂ (SEQ ID NO: 281) N-α-Ac- [Phe ²⁷ ] PYY (22-36) N-α-Ac-ASLRH [Thz] [Phe] LNLVTRQRY-NH ₂ (SEQ ID NO: 282) N-α-Ac- [Phe ²⁷ ] PYY (22-36) N-α-Ac- [Phe] SLRN [Phe] LNLVTRQRY-NH ₂ (SEQ ID NO: 289) N-α-Ac- [Tyr ²² , Phe ²⁷ ] PYY (22-36) N-α-Ac- [Tyr] SLRH [Phe] LNLVTRQRY-NH ₂ (SEQ ID NO: 290) N-α-Ac- [Trp ²⁸ ] PYY (22-36) N-α-Ac-ASLRHY [Trp] NLVTRQRY-NH ₂ (SEQ ID NO: 291) N-α-Ac- [Trp ²⁸ ] PYY (22-36) N-α-Ac-ASLRHYLN [Trp] VTRQRY-NH ₂ (SEQ ID NO: 292) N-α-Ac- [Ala ²⁶ , Phe ²⁷ ] PYY (22-36) N-α-Ac-ASLR [Ala] [Phe] LNLVTRQRY-NH ₂ (SEQ ID NO: 293) N-α-Ac- [Bth ²⁷ ] PYY (22-36) N-α-Ac-ASLR [Bth] LNLVTRQRY-NH ₂ (SEQ ID NO: 294) N-α-Ac- [Phe ²⁷ ] PYY (22-36) N-α-Ac-ASLRH [Phe] LNLVTRQRY-NH ₂ (SEQ ID NO: 295) N-α-Ac- [Phe ^27.36 ] PYY (22-36) N-α-Ac-ASLRH [Phe] LNLVTRQR [Phe] -NH ₂ (SEQ ID NO: 296) N-α-Ac- [Phe ²⁷ , D-Trp ³² ] PYY (22-36) N-α-Ac-ASLRH [Phe] LNLVIT) -Trp] RQRY-NH ₂ (SEQ ID NO: 297)

Other PYY agonists include neutrophilic receptor YY2-specific peptides having the formula:

X1 (-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14) _n -X15, where X1-NH, CH ₃ CO or one or two natural amino acids.

X2 - Leu, Ile or Val.

X3 is Arg, Lys or His.

X4 is His, Lys or Arg.

X5 - Tyr or Phe.

X6 - Leu, Ile or Val.

X7 - Asn or Gln.

X8 - Leu, Ile or Val.

X9 - Leu, Ile or Val.

X10 is Thr or Ser.

X11 is Arg, His or Lys.

X12 - Gln or Asn.

X13 - Arg, His or Lys.

X14 - Tyr or Phe.

X15 — COOH, NH _2, or one or two naturally occurring amino acids with a terminal amino acid in normal or carboxamide form, and n = 1-5. See U.S. Patent No. 5,696,093.

Examples of agonists include:

CH ₃ CO-LRHYLNLLTRQRY-NH ₂ (SEQ ID NO: 298)

CH ₃ CO-LRHYINLITRQRY-NH ₂ (SEQ ID NO: 299)

NH ₂ -LRHYLNLLTRQRY-NH ₂ (SEQ ID NO: 300)

NH ₂ -LRHYINLITRQRY-NH ₂ (SEQ ID NO: [301)

Other PYY agonists have the formula:

N-α-R ₁ - [Nle ^24.28.30 , Trp ²⁷ , Nva ³¹ , ψ ^35/36 ] PYY (22-36) -NH ₂ ,

N-α-R ₁ - [Nle ^24.28 , Trp ^27.30 , Nva ³¹ , ψ ^35/36 ] PYY (22-36) -NH ₂ ,

N-α-R ₁ - [Nle ^24.28.30 , Phe ²⁷ , Nva ³¹ , ψ ^35/36 ] PYY (22-36) -NH ₂ ,

N-α-R ₁ - [Nle ^24.28 , Phe ²⁷ , Trp ³⁰ , Nva ³¹ , ψ ^35/36 ] PYY (22-36) -NH ₂ ,

N-α-R ₁ - [Trp ³⁰ , ψ ^35/36 ] PYY (25-36) -NH ₂ ,

N-α-R ₁ - [Trp ³⁰ ] PYY (25-36) -NH ₂ ,

N-α-R ₁ - [Nle ^24.28 , Trp ³⁰ , Nva ³¹ , ψ ^35/36 ] PYY (22-36) -NH ₂ and

N-α-R ₁ - [Nle ²⁸ , Trp ³⁰ , Nva ³¹ , ψ ^35/36 ] PYY (22-36) -NH ₂ or their pharmaceutically acceptable salts,

where R ₁ is H, (C _1-12 ) -alkyl or (C _1-12 ) -acyl and

ψ is a pseudopeptide bond selected from the group consisting of -CH ₂ -NH--, --CH ₂ -S--, --CH ₂ -CH ₂ -, --CH ₂ --O-- and - CH ₂ --CO--. See U.S. Patent No. 6046162.

In specific compounds of the group of compounds described in the preceding paragraph, R ₁ is acetyl and ψ - --CH ₂ -NH--.

A particular selection of compounds is selected from the group consisting of

N-α-Ac- [Nle ^24.28.30 , Trp ²⁷ , Nva ³¹ , ψ ^35/36 ] PYY (22-36) -NH ₂ , (SEQ ID NO: 302)

N-α-Ac- [Nle ^24.28 , Trp ^27.30 , Nva ³¹ , ψ ^35/36 ] PYY (22-36) -NH ₂ , (SEQ ID NO: 303)

N-α-Ac- [Nle ^24.28.30 , Phe ²⁷ , Nva ³¹ , ψ ^35/36 ] PYY (22-36) -NH ² , (SEQ ID NO: 304)

N-α-Ac- [Nle ^24.28 , Phe ²⁷ , Trp ³⁰ , Nva ³¹ , ψ ^35/36 ] PYY (22-36) -NH ₂ , (SEQ ID NO: 305)

N-α-Ac- [Trp ³⁰ , ψ ^35/36 ] PYY (25-36) -NH ₂ , (SEQ ID NO: 306)]

N-α-Ac- [Trp ³⁰ ] PYY (25-36) -NH ₂ (SEQ ID NO: 307) and

N-α-Ac- [Nle ²⁸ , Trp ³⁰ , Nva ³¹ , ψ ^35/36 ] PYY (22-36) -NH ₂ , (SEQ ID NO: 308) or their pharmaceutically acceptable salts.

Another specific compound has the formula N-α-Ac- [Nle ^24.28 , Trp ³⁰ , Nva.sup. ³¹ , ψ ^35/36 ] PYY (22-36) -NH ₂ (SEQ. ID. NO: 309) or a pharmaceutically acceptable salt thereof.

Another PYY agonist has the formula (A),

containing one or two pseudo-peptide bonds, where each pseudo-peptide bond is independently selected from the group consisting of -CH ₂ -NH--, --CH ₂ -S--, --CH ₂ --CH ₂ -, --CH ₂ -O-- and -CH ₂ -CO--, where:

R ₁₀ is a chain of 0-5 amino acids, including a chain in which the N-terminal amino acid is linked to R ₁ and R ₂ through the side chain of the N-terminal amino acid or nitrogen of the amino group of the N-terminal amino acid;

R ₂₀ is a chain of 0-4 amino acids, including a chain in which the C-terminal amino acid is linked to R ₃ and R ₄ through the side chain of the C-terminal amino acid or the carbon atom of the carboxyl group of the C-terminal amino acid;

Each of R ₁ , R ₂ , R ₃ and R _{4 are} independently selected from the group consisting of H, (C ₁ -C ₁₂ ) -alkyl, (C ₆ -C ₁₈ ) -aryl, (C ₁ -C ₁₂ ) - acyl, phenyl (C ₁ -C ₁₂ ) -alkyl and ((C ₁ -C ₁₂ ) alkyl) _1-5- phenyl;

A ²² is an aromatic amino acid, Ala, Aib, Anb, N-Me-Ala or a deletion;

A ²³ is Ser, Thr, Ala, N-Me-Ser, N-Me-Thr, N-Me-Ala or a deletion;

A ²⁴ - Leu, Ile, Nle, Val, Trp, Gly, Aib, Anb, N-Me-Leu or a deletion;

A ²⁵ is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-p .∈-NH-Z, Orn or a deletion;

A ²⁶ - His, Thr, 3-Me-His, 1-ME-His, β-pyrazolylalanine, N-Me-His, Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-∈-NH-Z , Orn or deletion; A ²⁸ - Leu, Ile, Nle, Val, Trp, Aib, Anb or N-Me-Leu;

A ²⁹ - Asn, Ala, Gln Gly, Trp or N-Me-Asn;

A ³⁰ - Leu, Ile, Nle, Fla, Val, Trp, Aib, Anb or N-Me-Leu;

A ³¹ - Val, Nva, Ile, Trp, Aib, Anb or N-Me-Val and

A ³² - Thr, Ser, N-Me-Ser or N-Me-Thr,

where Z for each case are independently selected from the group consisting of H, (C ₁ -C ₁₀ ) -alkyl and (C ₆ -C ₁₈ ) -aryl or a pharmaceutically acceptable salt thereof. See U.S. Patent No. 6046167.

In a sample of specific compounds of the group of compounds described in the preceding paragraph, R ₁₀ - A ¹⁷ -A ¹⁸ -A ¹⁹ -A ²⁰ -A ²¹ ,

where A ¹⁷ is Cys, Leu, Ile, Val, Nle, Nva, Aib, Anb or N-Me-Leu;

A ¹⁸ is Cys, Ser, Thr, N-Me-Ser or N-Me-Thr;

A ¹⁹ is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-∈-NH-Rg, Cys or Orn;

A ²⁰ is an aromatic amino acid or Cys;

A ²¹ is an aromatic amino acid or Cys;

R ₂₀ - A ³³ -A ³⁴ -A ³⁵ -A ³⁶ ,

A ³³ is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-∈-NH-R ₅ , Cys or Orn;

A ³⁴ Cys, Gln, Asn, Ala, Gly, N-Me-Gln, Aib or Anb;

A ³⁵ is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-∈-NH-R ₅ , Cys or Orn and

A ³⁶ is an aromatic amino acid or Cys,

where R ₅ for each case are independently selected from the group consisting of H ₁ , (C ₁ -C ₁₀ ) -alkyl and (C ₆ -C ₁₈ ) -aryl.

A selection of specific compounds of the preceding group is represented by compounds of the formula N-α-Ac- [Fla ²⁷ ] PYY (25-36) -NH ₂ and N-α-Ac- [Fla ²⁷ ] PYY (22-36) -NH ₂ or its pharmaceutically acceptable salt.

Another group of PYY agonists has the formula:

or its pharmaceutically acceptable salt, in which

------ represents an optional link between amino acids for which a link is shown to each other, where each link is independently selected from the group consisting of --S - S-- only when the linked amino acids are Cys-Cys, -CO-NH-, -CH ₂ -NH- and

provided that in the case where an optional relationship is submitted

it replaces two amino acids to which an optional bond is attached; q is 1-4; m is 1-4;

R ₃₀ is OH or —OR ₁ , provided that when A ¹ -A ^{7 is} removed, R ₃₀ may also be NH-R ₁ , where R _{30 is} attached to the carbon atom of the carboxyl C-terminal amino acid;

each of R ₁ and R ₂ for each case is independently selected from the group consisting of H, (C ₁ -C ₁₂ ) -alkyl, (C ₆ -C ₁₈ ) -aryl, (C ₁ -C ₁₂ ) acyl, phenyl - (C ₁ -C ₁₂ ) -alkyl and ((C ₁ -C ₁₂ ) -alkyl) _1-5- phenyl, wherein R ₁ and R _{2 are} attached to an amine nitrogen of an N-terminal amino acid;

A ^{1 is} removed or represented by the D or L forms of the following amino acids: Trp, Tyr, Fla, Bth, Nal, Tic, Tic-OH, Dip, Bip or optionally substituted Phe, where Phe is optionally substituted with one of five substituents selected from the group consisting of (C ₁ -C ₄ ) -alkyl, halogen, (C ₁ -C ₄ ) -alkoxy, amino and nitro groups;

A ^{2 is} deleted or represented by the D- or L-forms of the following amino acids: Il, Val, Leu, Nle, Anb, Aib, Pro, Gln or Asn;

A ^{3 is} deleted or represented by the D or L forms of the following amino acids: Asn, Gln Glu, Asp, Orn, Lys, Dpr or Cys;

A ^{4 is} deleted or represented by D- or L-forms of the following amino acids: Ilé, Val, Leu, Nle, Anb, Aib or Pro;

A ^{5 is} deleted or represented by the D or L forms of the following amino acids: Il, Val, Leu, Nle, Anb, Aib, Pro, Glu, Asp, Om, Lys, Dpr or Cys;

A ^{6 is} deleted or represented by the D or L forms of the following amino acids: Thr, Ser, Trp, Tyr, Fla, Bth, Nal, Tic, Tic-OH, Dip, Bip or optionally substituted Phe, where Phe is optionally substituted with one of five substituents selected from the group consisting of (C ₁ -C ₄ ) -alkyl, halogen, (C ₁ -C ₄ ) -alkoxy, amino and nitro groups;

A ^{7 is} deleted or represented by the D- or L-forms of the following amino acids: Arg, Lys, homo-Arg, dialkyl-homo-Arg, Lys-∈-NH-R7 or Orn;

A ^{8 is} deleted or represented by the D or L forms of the following amino acids: Nva, Val, Ile, Leu, Nle, Anb, Aib, Pro, Gln Asn, Glu, Asp, Orn, Lys, Dpr or Cys;

A ^{9 is} deleted or represented by D- or L-forms of the following amino acids: Arg, Lys, homo-Arg, dialkyl-homo-Arg, Lys-∈-NH-R7 or Orn and

A ^{10 is} deleted or represented by D- or L-forms of the following amino acids: Tyr, Trp, Fla, Bth, Nal, Tic, Tic-OH, Dip, Bip, tyramine or optionally substituted Phe, where Phe is optionally substituted with one of five substituents selected from the group consisting of (C ₁ -C ₄ ) -alkyl, halogen, (C ₁ -C ₄ ) -alkoxy, amino and nitro, or the corresponding decarboxylated optionally substituted Phe;

where R ₇ for each case is independently selected from the group consisting of H ₁ (C ₁ -C ₁₀ ) -alkyl and (C ₆ -C ₁₈ ) -aryl, provided that not all A ¹ -A ¹⁰ are removed simultaneously. See U.S. Patent No. 6046167.

A selection of specific compounds of the group of compounds presented in the immediately preceding paragraph contains

or a pharmaceutically acceptable salt thereof.

PYY and PYY agonists can be modified by well-known methods such as amidation, glycosylation, acylation (e.g. acetylation), sulfation, phosphorylation, cyclization, lipidization and pegylation. Methods for lipidizing fatty acid derivatives of sulfhydryl-containing compounds are disclosed in US Pat. 5936092, US Patent No. 6093692 and US Patent No. 6225445. Fatty acid derivatives of sulfhydryl-containing PYY and PYY agonists containing fatty acid conjugated products with a disulfide bond are used to deliver PYY and PYY agonists to nerve cells and tissues. This modification significantly increases the absorption of the compound relative to the absorption rate of unconjugated compounds, and also prolongs the retention of compounds in the blood and tissues. Moreover, the disulfide bond in the conjugate is very labile in the cells and, thus, facilitates the intracellular release of intact compounds from fatty acid molecules.

Fatty acids, as components of phospholipids, make up the bulk of cell membranes. Due to the lipid nature, fatty acids can easily penetrate into the cell membrane and interact with it without causing toxic effects. As a consequence, fatty acids are a potentially effective carrier ligand for the delivery of proteins and peptides. Strategic uses for fatty acids to deliver proteins and peptides include covalent modification of proteins and peptides and the use of fatty acid emulsions.

To obtain these conjugates, sulfhydryl-containing PYY and a PYY agonist are attached to the fatty acid derivative via a reversible biodegradable disulfide bond. It is believed that such a conjugate will bind to the apical side of the cell membrane, reach the basolateral membrane of the gastrointestinal epithelium as a result of membrane transport, and join the cycle with exit to the interstitial fluid as a result of restoration of the disulfide bond.

These lipidized compounds of PYY and a PYY agonist have the general formula

where P is the residue isolated from PYY or a PYY agonist; R ₁ is hydrogen, lower alkyl or aryl; R ₂ is a lipid-containing structure and R ₃ is -OH, a lipid-containing structure or chain of amino acids containing 1 or 2 amino acids and ending in -CO ₂ H or -COR ₂ . See U.S. Patent No. 5936092. These conjugates are particularly effective in enhancing the absorption and prolongation of the retention of PYY and PYY agonists in the blood and tissues.

Typical alkyl groups include C ₁ -C ₆ alkyl groups, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl and the like.

Preferred aryl groups are C ₆ -C ₁₄ aryl groups and typically include phenyl, naphthyl, fluorenyl, phenanthryl and anthracyl groups.

The term "lipid-containing structure (molecule)" refers to either a lipid group as such or a hydrocarbon-based group (in particular, one or more amino acids) containing a lipid group. The term "lipid group" means a hydrophobic substituent containing 4-26 carbon atoms, preferably 5-19 carbon atoms. Suitable lipid groups include, but are not limited to, palmityl (C ₁₅ H ₃₁ ), oleyl (C ₁₅ H ₂₉ ), stearyl (C ₁₇ H ₃₅ ), cholate and deoxycholate.

In PCT Application No. WO 00/34236 describes conjugates of a drug substance and a carrier and a synthesis strategy aimed at their preparation, as well as synthesis methods, intermediates and end products used for the administration and release of biologically active compounds containing amino groups. These lipidized compounds of PYY and PYY agonists have the general formula I

where R ₂ selected from the group consisting of hydrogen, halogen, alkyl or aryl, where the alkyl or aryl groups are optionally substituted by one or more alkoxygroup, alkoxyalkyl, alkanoyl, nitro group, cycloalkyl, alkenyl, alkynyl, alkanoyloxy, alkyl or halogen atoms;

R ₃ is a lipophilic group; one of R ₄ and R ₅ and PYY or an agonist of PYY and the others of

R ₄ and R ₅ are OR ₆ , where R ₆ is hydrogen, an alkali metal or a negative charge;

X is oxygen or sulfur;

Y - bridging natural or unnatural amino acid; n is zero or 1 and

m is an integer from 0 to 10.

Typical alkyl groups include C ₁ -C ₆ alkyl groups, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl and the like.

Typical alkoxy groups include oxygen substituted any of the above alkyl groups.

Typical alkoxyalkyl groups include any of the above alkoxy-substituted alkyl groups, such as methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, pentoxymethyl, hexoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl and the like.

Preferred aryl groups are C ₆ -C ₁₄ aryl groups and typically include phenyl, naphthyl, fluorenyl, phenanthryl and anthracyl groups.

Typical alkoxy substituted aryl groups include the above aryl groups substituted with one or more of the above alkoxy groups, for example 3-methoxyphenyl, 2-ethoxyphenyl, and the like.

Typical alkyl substituted aryl groups include any of the above aryl groups substituted with any of a C ₁ -C ₆ alkyl group, including a Ph (CH ₂ ) _n group, where n = 1-6, for example, toluene, o-, m- and p-xylyl, ethylphenyl, 1-propylphenyl, 2-propylphenyl, 1-butylphenyl, 2-butylphenyl, tert-butylphenyl, 1-pentylphenyl, 2-pentylphenyl, 3-pentylphenyl.

Typical alkenyl groups include C ₂ -C ₆ alkenyl groups, for example ethynyl, 2-propenyl, isopropenyl, 2-butenyl, 3-butenyl, 4-pentenyl, 3-pentenyl, 2-pentenyl, 5-hexenyl, 4-hexenyl, 3-hexenyl and 2-hexenyl groups.

Typical alkynyl groups include C ₂ -C ₆ alkynyl groups, for example ethynyl, 2-propenyl, 2-butynyl, 3-butynyl, 4-pentinyl, 3-pentynyl, 2-pentynyl, 5-hexynyl, 4-hexynyl, 3- hexynyl and 2-hexynyl groups.

Typical alkenyl or alkynyl substituted aryl groups include any of the above C ₆ -C ₁₄ aryl groups substituted with any of the above C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl groups, for example ethynylphenyl, 1-propenylphenyl, 2- propenylphenyl, 1-butenylphenyl, 2-butenylphenyl, 1-pentenylphenyl, 2-pentenylphenyl, 3-pentenylphenyl, 1-hexenylphenyl, 2-hexenylphenyl, 3-hexenylphenyl, ethynylphenyl, 1-propynylphenyl, 2-propynylphenylphenyl butynylphenyl, 1-pentynylphenyl w, pentinilfenilnuyu-2, 3-pentinilfenilnuyu, geksinilfenilnuyu-1, 2-geksinilfenilnuyu, 3-geksinilfenilnuyu group.

Typical halogen groups include fluorine, chlorine, bromine and iodine.

Typical halogen-substituted alkyl groups include C ₁ -C ₆ alkyl groups substituted with one or more fluorine, chlorine, bromine and iodine atoms, for example fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl and trichloromethyl groups.

Typical alkanoyl groups include C _1-5 C (= O) alkanoyl groups, for example acetyl, propionyl, butanoyl, pentanoyl and hexanoyl groups, or an arylalkanoyl group, for example, C _1-5 C (= O) alkanoyl group, substituted with any of the above aryl groups.

Typical cycloalkyl groups include C _3-8 cycloalkyl groups, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups.

The term "lipophilic group", as used in this context, refers to either a natural lipid as such, a hydrophobic branched or unbranched hydrocarbon containing from about 4 to about 26 carbon atoms, preferably from about 5 to about 19 carbon atoms, fatty acid or its ester, or to a surfactant. Suitable lipophilic groups include, but are not limited to, long chain alkanoyl groups, including palmitoyl (C ₁₅ H ₃₁ ), oleoyl (C ₁₅ H ₂₉ ), stearyl (C ₁₇ H ₃₅ ), lauryl (C ₁₁ H ₂₃ ), chol and myristoyl C ₁₃ H ₂₇ ).

The term "natural or non-natural amino acid" as used in this context, refers to any of the 21 natural amino acids, as well as to D-forms of amino acids blocked by L- and D-forms of amino acids, such as amino acids blocked by amidation or acylation substituted by amino acids (for example, amino acids substituted with alkyl groups or cycloalkyl groups, such as cyclopropyl or cyclobutyl, which create steric hindrances) in which the substitution introduces a conformational restriction into the amino acid. Preferred natural amino acids used in this invention, such as amino acids or components of a peptide or protein, are alanine, arginine, asparagine, aspartic acid, citrulline, cysteine, cystine, γ-glutamic acid, glutamine, glycine, histidine, isoleucine, norleucine, leucine lysine, methionine, ornithine, phenylalanine, proline, hydroxyproline, serine, threonine, tryptophan, tyrosine, valine, γ-carboxyglutamine or O-phosphoserine. Preferred non-natural amino acids used in this invention, such as amino acids or components of peptides or proteins, are any of the β-amino acids, for example, α-alanine, γ-aminobutyric acid, γ- (aminophenyl) butyric acid, α-aminoisobutyric acid, ∈ -aminocaproic acid, 7-aminoheptanoic acid, aminobenzoic acid, aminophenylacetic acid, aminophenylbutyric acid, cysteine (AFM), methionine sulfone, phenylglycine, norvaline, ornithine, delta-ornithine, r-nitro-1,2-phenylanilan agidroisoquinoline-3-carboxylic acid and thioproline.

The invention is also directed to methods for producing lipidized conjugates of PYY and PYY agonists, pharmaceutical compositions comprising lipidized conjugates of PYY and PYY agonists, and methods for increasing the delivery of amino group-containing PYY and PYY agonists to the cell.

Chemically modified derivatives of PYY and PYY agonists are also provided herein that may provide additional benefits, such as increased solubility, stability and circulation time of the polypeptides, or decreased immunogenicity (see US Patent No. 4179337). These modified derivatives include PYY and PYY agonists modified with pegylation. The terms “pegylated” and “pegylation” refer to the reaction process of a polyalkylene glycol, preferably an activated polyalkylene glycol, with an agent that facilitates the action, such as an amino acid, for example lysine, to form a covalent bond. Although "pegylation" is often carried out using polyethylene glycol or its derivatives, such as methoxypolyethylene glycol, the term is not limited to this agent and is intended to include any other effective polyalkylene glycol, such as polypropylene glycol.

Derivative chemical structures can also be selected from water-soluble polymers such as polyethylene glycol, ethylene glycol / propylene glycol copolymers, carboxymethyl cellulose, dextran, polyvinyl alcohol and the like. The polypeptides can be modified at random positions of the molecule or at specified positions of the molecule and may include one, two, three or more attached chemical molecules.

The polymer may have any molecular weight and may be branched or unbranched. For polyethylene glycol, a preferred molecular weight is between about 1 kD and about 100 kD (the term “approximately” indicates that some molecules in the polyethylene glycol preparations will have a mass greater or slightly less than the indicated molecular weight) for ease of handling and manufacture. You can use other values depending on the desired therapeutic profile (for example, the desired duration of the delayed release, effects, if any, on biological activity, ease of handling, degree or absence of antigenicity and other known effects of polyethylene glycol on a therapeutic protein or analog). For example, polyethylene glycol may have an average molecular weight of approximately 200, 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, 10000 , 10500, 11000, 11500, 12000, 12500, 13000, 13500, 14000, 14500, 15000, 15500, 16000, 16500, 17000, 17500, 18000, 18500, 19000, 19500, 20,000, 25,000, 30,000, 35,000, 40,000, 50,000 , 55000, 60,000, 65,000, 70,000, 75,000, 80,000, 85,000, 90,000, 95,000 or 100,000 kD.

As indicated above, polyethylene glycol may have a branched structure. Branched polyethylene glycols are described, for example, in US Pat. 5,643,575; Morpurgo et al., Appl. Biochem. Biotechnol., 56: 59-72, (1996); Vorobjev et al., Nucleosides Nucleotides, 18: 2745-2750, (1999) and Caliceti et al., Bioconjug. Chem., 10: 638-646, (1999).

Polyethylene glycol molecules (or other chemical structures) should be attached to the polypeptides and protein, taking into account the effects on the functional and antigenic domains of the polypeptides or proteins. There are a number of attachment methods available to those skilled in the art, for example, see EP 0401384 (PEG binding to G-CSF), see also Malik et al., Exp. Hematol., 20: 1028-1035, (1992) (pegylation of GM-CSF using tresyl chloride is described). For example, polyethylene glycol can be covalently linked via amino acid residues via a reaction group, such as a free amino or carboxyl group. The reaction groups are represented by groups to which an activated polyethylene glycol molecule may be linked. Amino acid residues having a free amino group may include lysine residues and N-terminal amino acid residues; residues having a free carboxyl group may include aspartic acid residues, glutamic acid residues and C-terminal amino acid residues. Sulfhydryl groups can also be used as a reaction group for the addition of polyethylene glycol molecules. Preferred for therapeutic purposes is an attachment to an amino group, such as an attachment to the N-terminus or a lysine group.

As suggested above, polyethylene glycol can be attached to proteins and polypeptides by linking to any of a number of amino acid residues. For example, polyethylene glycol can be bound to proteins and polypeptides by covalent bonding to residues of lysine, histidine, aspartic acid, glutamic acid, or cysteine. One or more reaction methods can be used to attach polyethylene glycol to specific amino acid residues (e.g., lysine, histidine, aspartic acid, glutamic acid or cysteine) of a polypeptide or protein, or to more than one type of amino acid residues (e.g., lysine, histidine, aspartic acid, glutamic acid or cysteine, or combinations thereof) of a protein or polypeptide.

Proteins and polypeptides chemically modified at the N-terminus may be specifically required. Using the example of polyethylene glycol, a choice can be made among a variety of polyethylene glycol molecules (by molecular weight, branching, etc.), the ratio of polyethylene glycol molecules and protein (or peptide) molecules in the reaction mixture, the type of pegylation reaction carried out and the method for producing the selected pegylated protein N-end. A method for producing a preparation pegylated at the N-terminus (i.e., separating, if necessary, a given molecule from other mono-pegylated molecules) may include purifying the material pegylated at the N-terminus from a population of pegylated protein molecules. Selective proteins chemically modified by modification at the N-terminus can be obtained by alkylation using differences in the reactivity of different types of primary amino groups (lysine relative to the N-terminus) available for derivatization in a particular protein. Under appropriate conditions of the reaction, an almost selective N-terminal derivatization of the protein by a polymer containing a carbonyl group is achieved.

As indicated above, pegylation of proteins and polypeptides can be carried out by any number of methods. For example, polyethylene glycol can be attached to a protein or polypeptide either directly or using an intermediate linker. Linkerless systems for the attachment of polyethylene glycol to proteins and polypeptides are described in Delgado et al., Crit. Rev. Thera. Drug Carrier Sys., 9: 249-304, (1992), Francis et al., Intern. J. of Hematol., 68: 1-18, (1998); U.S. Pat. 4002531, US Patent No. 5349052, patent applications WO 95/06058 and WO 98/32466.

One of the systems for attaching polyethylene glycol directly to amino acid residues of proteins and polypeptides without an intermediate linker uses trisylated MPEG, which is obtained by modifying monomethoxypolyethylene glycol (MPEG) with tresyl chloride (ClSO ₂ CH ₂ CF ₃ ). In the reaction of a protein or polypeptide with trisylated MPEG, polyethylene glycol directly binds to the amine groups of the protein or polypeptide. Thus, the invention includes protein and polyethylene glycol conjugates resulting from the reaction of proteins and polypeptides with a polyethylene glycol molecule containing a 2,2,2-trifluorethanesulfonyl group.

Polyethylene glycol can also be attached to proteins and polypeptides using a number of different intermediate linkers. For example, U.S. Patent No. 5612460 discloses urethane linkers for binding polyethylene glycol to proteins. Protein and polyethylene glycol conjugates in which polyethylene glycol is attached to a protein or polypeptide via a linker can also be obtained by reacting proteins or polypeptides with compounds such as MPEG-succinimidyl succinate, MPEG activated by 1,1'-carbonyldimidazole, MPEG-2,4,5 trichlorophenyl carbonate, MPEG-r-nitrophenol carbonate and various derivatives of MPEG succinate. A number of additional derivatives of polyethylene glycol and chemical methods for the reaction of attaching polyethylene glycol to proteins and polypeptides are described in patent application WO 98/32466.

The number of polyethylene glycol molecules attached to each protein or polypeptide (i.e., degree of substitution) may also vary. For example, pegylated proteins and polypeptides can be associated on average with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 17, 20 or more polyethylene glycol molecules. Similarly, the average degree of substitution lies in such intervals as 1-3, 2-4, 3-5, 4-6, 5-7, 6-8, 7-9, 8-10, 9-11, 10-12, 11-13, 12-14, 13-15, 14-16, 15-17, 16-18, 17-19 or 18-20 polyethylene glycol molecules / protein or polypeptide molecule. Methods for determining substitution are discussed, for example, in Delgado et al., Crit. Rev. Thera. Drug Carrier Sys., 9: 249-304, (1992). Proteins and polypeptides containing substantially non-antigenic polymers, preferably polyalkylene glycols, can be prepared, for example, as described in US Pat. 5428128, US Patent No. 6,127,355 and U.S. Pat. 5880131.

In order to covalently bond polyethylene glycol (PEG) to a protein or polypeptide, the hydroxyl end groups of the PEG must first be converted into reactive functional groups. This process is often referred to as “activation” and the resulting product is called “activated PEG”. Often used methoxypolyethylene glycol (MPEG) with a distal cap in the form of a reaction functional group. One such activated PEG is a succinimidyl succinate derivative of PEG (SS-PEG). See also the article by Abuchowski et al., Cancer Biochem. Biophys., 7: 175-186, (1984) and U.S. Patent No. 5122614, which discloses polyethylene glycol-N-succinimide carbonate and its preparation.

Alternative substantially non-antigenic polymers that can be used in the practice of this invention include materials such as dextran, polyvinylpyrrolidones, polysaccharides, starches, polyvinyl alcohols, polyacrylamides or other similar non-immunogenic polymers. Competent specialists in this field will be aware that the foregoing is just an illustration and is not intended to limit the types of polymer substances suitable for use in this context.

In one aspect of the invention, the polymer is introduced into a peptide or protein molecule after it is functionalized or activated to react and attach to one or more amino acids. Ordinary specialists in this field by activation understand that the polymer is functionalized by including the desired reaction group. See, for example, U.S. Patent No. 4,179,337 and U.S. Pat. 5122614. In this embodiment, the hydroxyl end groups of the polyalkylene glycols are converted and activated to give reactive functional groups.

In another aspect of the invention, the polymer is conjugated to a reaction facilitating molecule before being introduced into the polypeptide or protein molecule. The reaction facilitating molecule is preferably an amino acid such as lysine, but non-amino acid molecules are also contemplated. Multifunctionalized organic molecules, such as alkyls or substituted alkyls, are included in this aspect. These molecules can be obtained that contain a nucleophilic functional group, such as an amine, and an electrophilic group, such as an acid, as well as a suitably functionalized site for conjugation with the desired polymer or polymers.

Molecules that facilitate the reaction, simplify the introduction of the polymer into the molecule of the peptide or protein in the synthesis. For example, polyalkylene glycols associated with facilitating the reaction of amino acids or amino acid residues in polypeptides or proteins with suitable binding agents are illustrative of the foregoing. A useful overview of a number of binding agents known in the art is provided by Dreborg et al. (see Critical Reviews in Therapeutic Drug Carrier Systems, 6 (4): 315-165, (1990), see, in particular, cc. 317-320).

Pegylated peptides and PYY agonists may also have the general formula

where D is the remainder of the peptide or PYY agonist;

X is a group that removes an electron;

Y and Y 'are independently represented by O or S;

(n) is zero (0) or a positive integer, preferably from 1 to about 12;

R ₁ and R _{2 are} independently selected from the group consisting of H, C _1-6 alkyls, aryls, substituted aryls, aralkyls, heteroalkyls, substituted heteroalkyls and substituted C _1-6 alkyls;

R ₃ is a substantially non-antigenic polymer, C _1-12 unbranched or branched alkyl or substituted alkyl, C _5-8 cycloalkyl or substituted cycloalkyl, carboxyalkyl, carboalkoxyalkyl, dialkylaminoalkyl, phenylalkyl, phenylaryl

and R ₄ and R _{5 are} independently selected from the group consisting of H, C _1-6 alkyls, aryls, substituted aryls, aralkyls, heteroalkyls, substituted heteroalkyls and substituted C _1-6 alkyls, or together they form a cyclic C ₅ -C _7- structure. See U.S. Patent No. 6127355.

Typical alkyl groups include C _1-6 alkyl groups, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, 2 -hexyl, 3-hexyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl and the like.

Preferred aryl groups are represented by C _6-14 aryl groups and typically include phenyl, naphthyl, fluorenyl, phenanthryl and anthracyl groups.

Typical alkyl substituted aryl groups include any of the above aryl groups substituted with any of a C _1-6 alkyl group, including a Ph (CH ₂ ) _n group, where n = 1-6, for example, toluene, o-, m and p-xylyl, ethylphenyl, 1-propylphenyl, 2-propylphenyl, 1-butylphenyl, 2-butylphenyl, tert-butylphenyl, 1-pentylphenyl, 2-pentylphenyl, 3-pentylphenyl.

Typical cycloalkyl groups include C _3-8 cycloalkyl groups, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups.

Typical electron removal groups include O, NR ₁ , S, SO, and SO ₂ , where R _{1 is} defined above.

PYY antagonists

The use of a Y receptor antagonist is also contemplated. A Y receptor antagonist is a substance (typically a ligand) that binds to the Y receptor and blocks the physiological effect of the Y receptor agonist (such as PYY, NPY, or PP (see Tables 1-3, above) These antagonists can be either peptide antagonists or non-peptide antagonists of PYY, NPY or PP.

The peptide antagonist includes modifications, mutants, fragments and / or variants of the natural amino acid sequence of the PYY, NPY or PP peptides (obtained, for example, by deletions, amino acid substitutions, deletions, insertions and modifications of the N-terminal amino and / or C-terminal carboxyl group ), which result in the formation of a peptide that acts as an antagonist of the Y receptor. In addition, the amino acid sequences PYY, NPY or PP can be fused or chimeric proteins that act as antagonists of the Y receptor. These peptides m Gut also be modified by processes such as lipidatsiya, pegylation, amidation, glycosylation, acylation, sulfation, phosphorylation, acetylation and cyclization.

Many non-peptide Y receptor antagonists are well known in the art and are intended to be used in this invention. (See Table 5 below). Any known non-peptide antagonists of PYY, NPY or PP can be used in this invention.

TABLE 5 - Antagonist of PYY and NPY

Examples of Y receptor antagonists include, but are not limited to, the following compounds:

BIV03304

Link: see article Berglund, M.M. Biochem. Pharmacol. 60 (12): 1815-22, December 15, 2000

SR120819A

1- [2- [2- (2-naphthylsulfamoyl) -3-phenylpropionamido] -3- [4-N- [4- (dimethylaminomethyl) cis-cyclohexylmethyl] amidino] phenyl] propionyl] pyrrolidine, (S, R) stereoisomer

Link: see article Berglund, M.M. Biochem. Pharmacol. 60 (12): 1815-22, December 15, 2000

BIIE0246

(S) -N2 - [[1- [2- [4 - [(R, S) -5,11-dihydro-6 (6h) -oxodibenz [b, e] azepin-11-yl] -1-piperazinyl ] -2-oxoethyl] cyclopentyl] acetyl] -N- [2- [1,2-dihydro-3,5 (4H) -dioxo-1,2- [diphenyl-3H-1,2,4-triazole-4 -yl] ethyl] -argininamide

Ref: Malmstrom, Life Sci., 69 (17): 1999-2005, September 14, 2001

BIBP 3226

[(R) -N2- (diphenylacetyl) -N - [(4-hydroxyphenyl) methyl] -D-arginine amide] and the recently described peptide structure [Ile-GLU-PRO-ORN-Tyr-Arg-Leu-Arg- Tyr-NH2, cyclic (2,4 '), (2', 4) -diamide].

Reference: see article Doods, N. N. J. Pharmacol. Exp.Ther., 275 (1): 136-42, October 1995.

BIBP 3435

Reference: see article Lundberg J. M., ModinA., Br.J. Pharmacol., 116 (7): 2971-82, December 1995.

H 394/84

1,4-dihydro-4- [3 - [[[[[3- [spiro (inden-4,1'-piperidin-1-yl)] propyl] amino] carbonyl] amino] phenyl] dimethyl ester], 6-dimethyl-3,5-pyridine-dicarboxylic acid

Link: see article Malmstrom R. E., Eur. J. Pharmacol., 418 (1-2): 95-104, April 20, 2001.

H 409/22

(2R) -5 - ([amino (imino) methyl] amino) -2 - [(2,2-diphenylacetyl) amino] -N - [(IR) -1- (4-hydroxyphenyl) ethyl] -pentanamide

Link: see article Malmstrom R. E. Life Sci., 69 (17): 1999-2005, September 14, 2001

1229U91

Reference: see article Schober D. A., Peptides, 19 (3): 537-42, 1998.

L-152804

Reference: see Kanatani A. Biochem article. Biophys. Res. Commun., 272 (1): 169-73, May 27, 2000

Aminoalkyl-substituted pyrazolo- [1,5, a] -1,5-pyrimidines and pyrazolo- [1,5-a] -1,3,5-triazines

Reference: US Patent No. 6372743

Alkyl and cycloalkyl derivatives of 1,4-dihydropyridine (e.g. dimethyl ester

1,4-dihydro-2,6-dimethyl-4- [4 - [[[[3- [4- (3-methoxyphenyl) -1-piperidinyl] propyl] amino] carbonyl] amino] butyl] -3.5 -pyridine-carboxylic acid)

Reference: US Patent NO. 6444675

Derivatives of [4- (3-substituted phenyl) -1,4-dihydropyridine

Reference: US Patent No. 5635503

Derivatives of 4-phenyl-1,4-dihydropyridines dimethyl ester e.g.

1,4-dihydro-4- [3 - [[2 - [[3- [4- (3-methoxyphenyl) -1-piperidinyl] propyl] amino] -3,4-dioxo-1-cyclobuten-1-yl ] amino] phenyl] -2,3-dimethyl-3,5-pyridinedicarboxylic acid

Reference: US Patent NO. 6432960

A substituted amide-based Y receptor antagonist, such as:

N- (4-diethylamino-phenyl) -2-phenyl-2-pyridin-4-yl-acetamide;

2- (4-fluorophenyl) -2-pyridin-4-yl-N- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-5'-yl) -acetamide;

2-phenyl-2-pyridin-4-yl-N- (3,4,5,6-tetrahydro-2H- [1,2 '] - bipyridinyl-5'-yl) -acetamide;

N- (4-diethylamino-phenyl) -2-phenyl-2-pyridin-2-yl-acetamide;

N- (6-diethylamino-pyridin-3-yl) -2,2-diphenylacetamide;

N- (4-diethyl-sulfamoyl-phenyl) -2-phenyl-2-pyridin-4-yl-acetamide;

2,2-diphenyl-N- (6-pyrrolidin-1-yl-pyridin-3-yl) -acetamide;

2,2-diphenyl-N- (3,4,5,6-tetrahydro-2H- [1,2 '] - bipyridinyl-5'-yl) -acetamide;

N- [6- (2,5-Dimethyl-pyrrolidin-1-yl) -pyridin-3-yl] -2,2-diphenyl-acetamide;

N- (4-diethylsulfamoyl-phenyl) -2,2-diphenyl-acetamide and

N- (4-Dimethylsulfamoyl-phenyl) -2,2-diphenyl-acetamide.

Reference: US Patent No. 6407120 Carbazole Y receptor antagonist, such as:

2-dimethylamino-N- (9-ethyl-9H-carbazol-3-yl) -acetamide;

3-diethylamino-N- (9-ethyl-9H-carbazol-3-yl) propionamide;

N- (9-ethyl-9H-carbazol-3-yl) -2-fluoro-benzamide;

4-dimethylamino-N- (9-ethyl-9H-carbazol-3-yl) butyramide;

N- (9-ethyl-9H-carbazol-3-yl) -2-hydroxy-2,2-diphenyl-acetamide;

N- (9-ethyl-9H-carbazol-3-yl) -2-hydroxy-2-methyl-propionamide;

N- (9-ethyl-9H-carbazol-3-yl) -2-hydroxy-2-methyl-butyramide;

N- (9-ethyl-9H-carbazol-3-yl) -2-hydroxy-2-phenyl-propionamide;

(R) -N- (9-ethyl-9H-carbazol-3-yl) -2-hydroxy-2-phenyl-propionamide;

2-bromo-N- (9-ethyl-9H-carbazol-3-yl) -acetamide and

3-dimethylamino-N- (9-ethyl-9H-carbazol-3-yl) -propionamide.

2- [bis- (2-hydroxyethyl) amino] -N- (9-ethyl-9H-carbazol-3-yl) -acetamide;

2-benzylamino-N- (9-ethyl-9H-carbazol-3-yl) -acetamide;

3-diphenylamino-N- (9-ethyl-9H-carbazol-3-yl) propionamide and

N- (9-ethyl-9H-carbazol-3-yl) -3- (4-piperidin-1-ylmethyl-phenoxy) propionamide;

N- (9-ethyl-9H-carbazol-3-yl) -3- [methyl- (1,2,3,4-tetrahydro-naphthalen-2-yl) amino] propionamide;

N- (9-ethyl-9H-carbazol-3-yl) -3- (quinolin-7-yloxy) -propionamide and

2- [bis- (2-hydroxyethyl) amino] -N- (9-ethyl-9H-carbazol-3-yl) -acetamide.

3-bromo-N- (9-ethyl-9H-carbazol-3-yl) propionamide;

N- (9-Isopropyl-9H-carbazol-3-yl) trifluoroacetamide;

4-dimethylamino-N- (9-ethyl-9H-carbazol-3-yl) -N-methyl-butyramide;

N- (9-methyl-9H-carbazol-3-yl) trifluoroacetamide;

1-hydroxy-cyclopropanecarboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide and

2- (4-chloro) benzylamino-N- (9-ethyl-9H-carbazol-3-yl) -acetamide.

2- (4-fluoro) benzylamino-N- (9-ethyl-9H-carbazol-3-yl) -acetamide;

(R) -N- (9-ethyl-9H-carbazol-3-yl) -2- (1-phenyl-ethylamino) -acetamide;

(R) -N- (9-ethyl-9H-carbazol-3-yl) -2- (1- (4-chloro) phenyl-ethylamino) -acetamide;

2- (3-diethylamino-2-hydroxy-propylamino) -N- (9-ethyl-9H-carbazol-3-yl) -acetamide;

2- (benzyl-isopropyl-amino) -N- (9-ethyl-9H-carbazol-3-yl) -acetamide;

N-3-bromo- (9-ethyl-9H-carbazol-6-yl) -trifluoroacetamide;

N- (9-ethyl-6-formyl-9H-carbazol-3-yl) trifluoroacetamide;

N- (9-ethyl-6-hydroxymethyl-9H-carbazol-3-yl) trifluoroacetamide;

N- (9-ethyl-9H-carbazol-3-yl) methanesulfonamide;

N- (9-ethyl-9H-carbazol-3-yl) -chloromethanesulfonamide;

2-bromo-N- (9-ethyl-9H-carbazol-3-yl) -acetamide and

3-dimethylamino-N- (9-ethyl-9H-carbazol-3-yl) -propionamide.

2- [bis- (2-hydroxy-ethyl) amino] -N- (9-ethyl-9H-carbazol-3-yl) -acetamide;

2-benzylamino-N- (9-ethyl-9H-carbazol-3-yl) -acetamide;

3-diphenylamino-N- (9-ethyl-9H-carbazol-3-yl) propionamide;

N- (9-ethyl-9H-carbazol-3-yl) -3- (4-piperidin-1-ylmethyl-phenoxy) propionamide;

N- (9-ethyl-9H-carbazol-3-yl) -3- [methyl- (1,2,3,4-tetrahydro-naphthalen-2-yl) amino] propionamide;

N- (9-ethyl-9H-carbazol-3-yl) -3- (quinolin-7-yloxy) -propionamide;

2- [bis- (2-hydroxy-ethyl) amino] -N- (9-ethyl-9H-carbazol-3-yl) -acetamide;

3-bromo-N- (9-ethyl-9H-carbazol-3-yl) -propionamide and

N- (9-Isopropyl-9H-carbazol-3-yl) -acetamide.

4-dimethylamino-N- (9-ethyl-9H-carbazol-3-yl) -N-methyl-butyramide;

N- (9-methyl-9H-carbazol-3-yl) trifluoroacetamide;

1-hydroxy-cyclopropanecarboxylic acid- (9-ethyl-9H-carbazol-3-yl) -amide;

2- (4-chloro) benzylamino-N- (9-ethyl-9H-carbazol-3-yl) -acetamide and

2- (4-fluoro) benzylamino-N- (9-ethyl-9H-carbazol-3-yl) -acetamide.

(R) -N- (9-ethyl-9H-carbazol-3-yl) -2- (1-phenyl-ethylamino) -acetamide;

(R) -N- (9-Ethyl-9H-carbazol-3-yl) -2- (1- (4-chloro) phenyl-ethylamino) -acetamide;

(R) -, (S) - or a mixture of (R) - and

(S) -2- (3-diethylamino-2-hydroxy-propylamino) -N- (9-ethyl-9H-carbazol-3-yl) -acetamide;

(S) -N- (6-tert-butyl-9-ethyl-9H-carbazol-3-yl) -2- (3-diethylamino-2-hydroxy-propylamino) -acetamide,

2- (benzyl-isopropyl-amino) -N- (9-ethyl-9H-carbazol-3-yl) -acetamide;

N-3-bromo- (9-ethyl-9H-carbazol-6-yl) trifluoroacetamide;

N- (9-ethyl-6-formyl-9H-carbazol-3-yl) trifluoroacetamide and

N- (9-ethyl-6-hydroxymethyl-9H-carbazol-3-yl) trifluoroacetamide.

N- (9-ethyl-9H-carbazol-3-yl) methanesulfonamide and

N- (9-ethyl-9H-carbazol-3-yl) -chloromethanesulfonamide.

Reference: see US Patent No. 6399631 Various dihydropyridine derivatives:

Reference: see US Patent No. 4829076

4- (3-substituted phenyl) -1,4-dihydropyridines cyanoguanidine derivatives

Reference: see US Patent No. 6001836

Amide derivatives that are antagonists of the Y5 NPY receptor

Reference: see US Patent No. 6410792

Thiourea-related piperazine and piperidine derivatives of 4-phenyl-1,4-dihydropyridines, such as 1,4-dihydro-4- [3 - [[[[3- [4- (3-methoxyphenyl) piperidinyl] dimethyl ester propyl] amino] carbonothioyl] amino] phenyl] -2,6-dimethyl-3,5-pyridine-dicarboxylic acid, dimethyl ester,

1,4-dihydro-4- [3 - [[[[3- (4-phenylpiperidinyl) propyl] amino] kaobonothioyl] amino] phenyl] -2,6-dimethyl-3,5-pyridine-dicarboxylic acid and

dimethyl ester

1,4-dihydro-4- [4 - [[[[3- (4-cyclohexyl-1-piperazinyl) propyl] amino] carbonothioyl] amino] phenyl] -2,6-dimethyl-3,5-pyridinedicarboxylic acid.

dimethyl ester

1,4-dihydro-4- [4-fluoro-3 - [[[[3- (4-phenylpiperidinyl) propyl] amino] carbonothioyl] amino] phenyl] -2,6-dimethyl-3,5-pyridine-dicarboxylic acids

dimethyl ester

1,4-dihydro-4- [3 - [[[[3- (4-methyl-1-piperidinyl) propyl] amino] carbonothioyl] amino] -4-fluorophenyl) -2,6-dimethyl-3,5- pyridine dicarboxylic acid,

dimethyl ester

1,4-dihydro-4- [3 - [[[[[3- (4-ethyl-1-piperidinyl] propyl] amino] carbonothioyl] amino] -4-fluorophenyl] -2,6-dimethyl-3,5 -pyridine-dicarboxylic acid,

dimethyl ester

1,4-dihydro-4- [3 - [[[[[3- (4-propyl-1-piperidinyl) propyl] amino] carbonothioyl] amino] -4-fluorophenyl] -2,6-dimethyl-3,5 -pyridine-dicarboxylic acid,

dimethyl ester

1,4-dihydro-4- [3 - [[[[3- [4-1,1-dimethylethyl) -1-piperidinyl] propyl] amino] carbonothioyl] amino] -4-fluorophenyl] -2,6-dimethyl -3,5-pyridinedicarboxylic acid,

dimethyl ester

1,4-dihydro-4- [3 - [[[[3- [4- (1-methylethyl) -1-piperidinyl] propyl] amino] carbonothioyl] amino] -4-fluorophenyl] -2,6-dimethyl- 3,5-pyridine-dicarboxylic acid and

dimethyl ester

1,4-dihydro-4- [4 - [[[[3- (4-cyclohexyl-1-piperazinyl) propyl] amino] carbonothioyl] amino] -4-fluorophenyl] -2,6-dimethyl-3,5- pyridine dicarboxylic acid.

Reference: see US Patent No. 6391881

New arylsulfonamide and sulfamide compounds

Reference: see US Patent No. 6391877

Amine and amide derivatives of a Y receptor antagonist, such as:

Amino-6 - [(2-fluorophenylsulfonyl) amino] -N- [cis-1,2,3,4-tetrahydro-6-methoxy-1- (3-pyridinylmethyl) -2-naphthenyl] - (2S) -hexanamide bis hydrochloride,

N- [5-amino-6 - [[cis-1,2,3,4-tetrahydro-6-methoxy-1- (3-pyridinylmethyl) -2 -] - naphthalenyl] amino] hexyl] -2-fluorobenzenesulfonamide Tris hydrochloride,

N- [5-amino-6- [cis-1,2,3,4-tetrahydro-6-hydroxy-1- (3-pyridinylmethyl) -2-naphthalenyl] amino] hexyl] -2-fluorobenzenesulfonamide tris hydrochloride,

(2S) -2- (acetylamino) -6 - [(2-fluorophenylsulfonyl) amino] -N- [cis-1,2,3,4-tetrahydro-6-methoxy-1- (3-pyridinyl methyl) -2 naphthenyl] hexanamide bis hydrochloride,

(2S) -2- (acetylamino) -6 - [(2-fluorophenylsulfonyl) amino] -N- [cis-1,2,3,4-tetrahydro-6-hydroxy-1- (3-pyridinylmethyl) -2- naphthenyl] hexanamide bis-hydrochloride,

3 - [(phenylsulfonyl) amino] -N- [cis-1,2,3,4-tetrahydro-6-fluoro-1- (3-pyridinylmethyl) -2-naphthalenyl] -1-pyrrolidinacetamide] bis-trifluoroacetate,

4-oxo-1-phenyl-N- [cis-1,2,3,4-tetrahydro-1- (3-pyridinylmethyl) -2-naphthalenyl] -1,3,8-triazaspiro [4.5] -decane-8 -acetamide bis-hydrochloride, trans-N- [2- (4-fluorophenyl) -3- (3-pyridinyl) propyl] -4 - [((2-fluoro-phenylsulfonyl) amino) methyl] -1-cyclohexanamide hydrochloride, trans-N - [[[[[2- (4-fluorophenyl) -3- (3-pyridinyl) propyl] amino] methyl] -4-cyclohexyl] methyl] 2-fluorobenzenesulfonamide bis-hydrochloride.

Reference: see US Patent No. 6380224.

Alkylenediamine-substituted pyrazole- (1,5-a) -1,5-pyrimidines and pyrazolo- (1,5-a) 1,3,5-triazines, such as:

[2- {2- [3- (2,6-dichloro-4-methoxyphenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-ylamino] ethylamino} -butan-1 -ol;

N-2- [3- (2,6-dichloro-4-methoxyphenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-ylamino] ethyl} -N'-methyl- cyclohexane-1,4-diamine;

N- {2- [3- (2,6-Dichloro-4-methoxyphenyl) -2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-ylamino] ethyl} -N'-ethyl- cyclohexane-1,4-diamine;

N- [3- (2,6-dichloro-4-methoxyphenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N- (4-morpholin-4-yl -cyclohexyl) ethane-1,2-diamine;

4- {2- [3- (2,6-dichloro-4-methoxyphenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-ylamino] ethylamino} cyclohexanol;

3- {2- [3- (2,6-dichloro-4-methoxyphenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-ylamino] ethylamino} propan-1, 2-diol;

N- {2- [3 (2,6-dichloro-4-methoxyphenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-ylamino] ethyl} -N'-isobutyl- cyclohexane-1,4-diamine;

N- {2- [3- (2,6-dichloro-4-methoxyphenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-ylamino] ethyl} -N-isobutyl- cyclohexane-1,4-diamine;

4- {2- [3- (2,6-dichloro-4-ethoxyphenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-ylamino] -1-methyl-ethylamino} - cyclohexanol;

2- {2- [3- (2,6-dichloro-4-ethoxyphenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-ylamino] ethylamino} cyclohexanol;

N- [3- (2,6-dichloro-4-methoxyphenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N- (4,4,4-trifluoro -butyl) ethane-1,2-diamine;

N- [3- (2,6-dichloro-4-ethoxyphenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N- (2,2,2-trifluoroethyl ) -ethane-1,2-diamine;

N- [3- (2,6-dichloro-4-methoxyphenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N- (2-trifluoromethyl-cyclohexyl) - ethane-1,2-diamine;

N- [3- (2,6-dichloro-4-methoxyphenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N- (4-trifluoromethyl-cyclohexyl) - ethane] -1,2-diamine;

N- [3- (2,6-dichloro-4-methoxyphenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N- (2,2-difluoroethyl ) -ethane-1,2-diamine;

N- [3- (2,6-dichloro-4-methoxyphenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N- (2-fluoro-1-methyl ethyl) ethane-1,2-diamine;

N- [3- (2,6-dichloro-4-methoxyphenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N- (2-fluoro-cyclohexyl) - ethane-1,2-diamine.

N- [3- (2,6-dichlorophenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N- (1-ethyl-piperidin-5-a] - pyrimidin-7-yl] -N- (2,2,6,6-tetramethyl-piperidin-4-yl) ethane-1,2-diamine;

N- [3- (2,6-dichloro-phenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N-19-piperidin-4-yl-ethane- 1,2-diamine;

N- [3- (2,6-dichlorophenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N- (1-ethyl-piperidin-3-yl) - ethylamine-1,2-diamine;

N- (1-benzyl-pyrrolidin-3-yl) -N '- [3- (2,6-dichlorophenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7- silt] ethane-1,2-diamine;

N- [3- (2,6-dichloro-phenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N'-pyrimidin-2-yl-ethan-1 2-diamine;

N- (1-benzylpiperidin-4-yl) -N '- [3- (2,4-dichloro-6-methoxyphenyl) -2,5-diethyl-pyrazolo- [1,5-a] pyrimidin-7- silt] ethane-1,2-diamine;

N- (1-benzyl-piperidin-4-yl) -N '- [3- (2,6-dichloro-4-methoxyphenyl) -2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7 -yl] ethane-1,2-diamine;

N- [3 (2,6-dichloro-4-methoxyphenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N- (1-methyl-piperidin-4- il) ethane-1,2-diamine;

N- [3- (2,6-dichloro-4-methoxyphenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N- (1-ethyl-piperidin-4 -yl) ethane-1,2-diamine;

N- [3- (2,6-dichloro-4-methoxyphenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N- (1-isopropyl-piperidin-4 -yl) ethane-1,2-diamine;

N- [3- (2,6-dichloro-4-methoxyphenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N- (2,2,6,6 -tetramethyl-piperidin-4-yl) ethane-1,2-diamine;

N- [3- (2,6-dichloro-4-methoxyphenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N- (1-ethyl-piperidine -3-yl) ethane-1,2-diamine;

N- [3- (2,6-dichlorop-4-methoxyphenyl) -2,5-dimethylpyrazole- [1,5-a] pyrimidin-7-yl] -N'-piperidin-4-yl ethane-1,2-diamine;

N.sup.2- (1-benzyl-piperidin-4-yl) -N '- [3- (2,6-dichloro-phenyl) -2,5-dimethyl-pyrazolo- [1,5-a] - pyrimidin-7-yl] propan-1,2-diamine;

N- [3- (2,6-dichloro-4-methoxyphenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N '- (1-pyridin- 3-yl-methyl-piperidin-4-yl) ethane-1,2-diamine;

N- [3- (2,6-Dichloro-4-methoxyphenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N '- (1-pyridin-4- ylmethyl-piperidin-4-yl) ethane-1,2-diamine;

3,5-dichloro-4-12,5-dimethyl-7-2- (1-phenyl-pyrrolidin-3-ylamino) ethyl] -pyrazolo- [1,5-A] pyrimidin-3-yl] - phenol;

N- [3- (2,6-dichloro-4-methoxyphenyl) -2,5-dimethyl-pyrazolo- [1,5-a] - pyrimidin-7-yl] -N '- (1-pyridin- 2-yl-methyl-piperidin-4-yl) ethane-1,2-diamine;

3,5-dichloro-4- (2,5-dimethyl-7- [2- (1-pyrimidin-2-yl-piperidin-4-ylamino) ethylamino] pyrazolo [1,5-a] pyrimidine -3-yl} benzonitrile;

N- [3- (2,6-dichloro-4-ethoxyphenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N '- (1-pyrimidine- 2-yl-piperidin-4-yl) ethane-1,2-diamine;

N- [3- (2,6-dichloro-4-methoxyphenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N '- (1-pyrimidine- 2-yl-piperidin-4-yl) ethane-1,2-diamine;

N- (1-benzyl-piperidin-4-yl) -N '- [3 (2,6-dichloro-4-ethoxy-phenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidine -7-yl] ethane-1,2-diamine;

N- [3- (2,6-Dichloro-phenyl) -5-ethyl-2-methyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N '- (1-pyrimidin-2- yl-piperidin-4-yl) ethane-1,2-diamine;

N- [3- (2,6-dichloro-phenyl) -5-isopropyl-2-methyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N '- (1-pyrimidin-2- yl-piperidin-4-yl) ethane-1,2-diamine;

N- [3- (2,4-Dichloro-phenyl) -5-isopropyl-2-methyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N '- (1-pyrimidin-2- yl-piperidin-4-yl) ethane-1,2-diamine;

N- [3- (2,6-dichloro-4-ethoxyphenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N- (1-pyrimidin-2 -yl-piperidin-4-yl) -propan-1,2-diamine;

N- [3- (2,6-Dichlorop-4-methoxyphenyl) -5-isopropyl-2-methyl-pyrazole- [1,5-a] pyrimidin-7-yl] -N2- (1-pyrimidine -2-yl-piperidin-4-yl) -propan-1,2-diamine;

N- [3- (2,6-Dichloro-4-methoxyphenyl) -5-ethyl-2-methylpyrazolo- [1,5-a] pyrimidin-7-yl] -N- (1-pyrimidin-2-yl piperidin-4-yl) ethane-1,2-diamine;

N- [3- (2,6-dichloro-4-methoxyphenyl) -2-methyl-5-propyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N- (1-pyrimidin-2 -yl-piperidin-4-yl) -propan-1,2-diamine;

N- [3- (2,6-dichloro-4-methoxyphenyl) -5-ethyl-2-methyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N- (1-pyrimidin-2 -yl-piperidin-4-yl) -propan-1,2-diamine;

N- [3- (2,6-dichloro-phenyl) -2-methyl-5-propylpyrazolo- [1,5-a] pyrimidin-7-yl-N '- (1-pyrimidin-2-yl-piperidine -4-yl) ethane-1,2-diamine;

N- [3- (2,6-dichloro-phenyl) -2-methyl-5-propyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N2- (1-pyrimidin-2-yl piperidin-4-yl) propan-1,2-diamine;

N- [3- (2,6-dichlorophenyl) -5-ethyl-2-methyl-pyrazolo- [1,5-a] pyrimidin-7-yl]

-N.sup.2- (1-pyrimidin-2-yl-piperidin-4-yl) -propan-1,2-diamine;

N- [5-ethyl-2-methyl-3- (2,4,6-trimethyl-phenyl) pyrazolo- [1,5-a] pyrimidin-7-yl] -N '- (1-pyrimidine- 2-yl-piperidin-4-yl) ethane-1,2-diamine;

N- [5-ethyl-2-methyl-3- (2,4,6-trimethyl-phenyl) -pyrazolo- [1,5-a] pyrimidin-7-yl] -N- (1-pyrimidin-2 -yl-piperidin-4-yl) -propan-1,2-diamine;

N- [3- (2,6-dichlorop-4-ethynylphenyl) -2,5-dimethylpyrazole- [1,5-a] pyrimidin-7-yl] -N '- (1-pyrimidin-2- yl-piperidin-4-yl) ethane-1,2-diamine;

N- [2-methyl-5-propyl-3- (2,4,6-trimethyl-phenyl) -pyrazolo- [1,5-a] pyrimidin-7-yl] -N '- (1-pyrimidine- 2-yl-piperidin-4-yl) ethane-1,2-diamine;

N- [2, [5-dimethyl-3- (2,4,6-trimethylphenyl) pyrazolo- [1,5-a] pyrimidin-7-yl] -N '- (1-pyridin-2-yl piperidin-4-yl) ethane-1,2-diamine;

N- [3- (2,6-dimethyl-phenyl) -5-ethyl-2-methyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N- (1-pyrimidin-2-yl piperidin-4-yl) propan-1,2-diamine;

N- [3- (2,6-dimethyl-phenyl) -2-methyl-5-propyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N- (1-pyrimidin-2-yl piperidin-4-yl) ethane-1,2-diamine;

N- [3- (2,6-dimethyl-phenyl) -2-methyl-5-propyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N2- (1-pyrimidin-2-yl piperidin-4-yl) propan-1,2-diamine;

N- [3- (2,6-dimethyl-phenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N- (1-pyrimidin-2-ylpiperidin-4 -yl) propane-1,2-diamine;

N- [3- (2,4-Dimethyl-phenyl) -5-ethyl-2-methyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N- (1-pyrimidin-2-yl piperidin-4-yl) ethane-1,2-diamine;

N- [3- (2,4-Dimethyl-phenyl) -2-methyl-5-propyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N- (1-pyrimidin-2-yl piperidin-4-yl) ethane-1,2-diamine and

[1- [4- (1 - {[3- (2,6-dichloro-4-methoxyphenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-ylamino] methyl] propylamino) piperidin-1-yl] ethanone.

N- [2,5-Dimethyl-3- (2,4,6-trimethylphenyl) pyrazolo- [1,5-a] pyrimidin-7-yl] -N- [2- (4-methoxyphenyl) ethyl ] ethane-1,2-diamine;

N- [3- (2,6-dichloro-4-methoxyphenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N- [2- (4-methoxyphenyl) ethyl] ethane-1,2-diamine;

N- [3- (2,6-dichloro-4-methoxyphenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N '- [2- (3-ethoxy -4-methoxyphenyl) ethyl] ethane-1,2-diamine;

N- [3- (2,6-dichloro-4-methoxyphenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N- [2- (4-ethoxy- 3-methoxyphenyl) ethyl] ethane-1,2-diamine;

N- [3- (2,6-dichlorop-4-methoxyphenyl) -2,5-dimethylpyrazole- [1-a] pyrimidin-7-yl] -N '- (1,2,3, 4-tetrahydro-naphthalen-2-yl) ethane-1,2-diamine;

N- [3- (2,6-dichloro-4-methoxyphenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N- (2-pyridin-2-yl ethyl) ethane-1,2-diamine;

N- [3- (2,6-dichloro-4-methoxyphenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N- (2-pyridin-3-yl -ethyl) -ethane-1,2-diamine and

N- [3- (2,6-dichloro-4-methoxyphenyl) -2,5-dimethyl-pyrazolo- [1,5-a] pyrimidin-7-yl] -N- (2-pyridin-4-yl ethyl) ethane-1,2-diamine.

Reference: US Patent No. 6372743

Spiroisoquinolinone derivative of antagonist Y, such as:

2- (3-chloropropyl) -2-phenyl-1,3-dioxolane,

2- (3-chloropropyl) -2- (4-methoxyphenyl) -1,3-dioxolane,

2- (3-chloropropyl) -2- (4-phenoxyphenyl) -1,3-dioxolane,

2- (3-chloropropyl) -2- (4-bromophenyl) -1,3-dioxolane,

2- (3-chloropropyl) -2- (4-chlorophenyl) -1,3-dioxolane,

N-3-chloropropyl-N-methylbenzenemethanamine hydrochloride,

N- (3-chloropropyl) -N- (phenylmethyl) benzenemethanamine hydrochloride,

N- (2-hydroxyethyl) -N-methylbenzolmethanamine,

chloro-1- (4-phenoxyphenyl) ethanone,

3-chloro-1- (4-phenoxyphenyl) propanone,

1 '- [3- (4-phenoxyphenyl) -3-oxopropyl] spiro [isoquinolin-1- (2H) -4'-piperidin-3- (4H) -one hydrochloride,

1 '- [3- (4-bromophenyl) -3-oxopropyl] spiro [isoquinolin-1- (2H) -4'-piperidin-3- (4H) -one],

1 '- [2 - [(1,1'-biphenyl) -4-yl] -2-oxoethyl] spiro [isoquinolin-1- (2H) -4'-piperidin-3- (4H) -one],

1 '- [2- (4-bromophenyl) -2-oxoethyl] spiro [isoquinolin-1- (2H) -4'-piperidin-3- (4H) -one],

1 '- [2- (4-phenoxyphenyl) -2-oxoethyl] spiro [isoquinolin-1- (2H-4'-piperidin-3- (4H) -one], hydrochloride,

1 '- [2- [bis (phenylmethyl) amino] ethyl] spiro [isoquinolin-1- (2H) -4'-piperidin-3- (4H) -one] dihydrochloride,

1 '- (4-phenyl-4-oxobutyl) spiro [isoquinolin-1- (2H) -4'-piperidin-3- (4H) one] hydrochloride,

1 '- [4- (4-methoxyphenyl) -4-oxobutyl] spiro [isoquinolin-1- (2H) -4'-piperidin-3- (4H) -one] hydrochloride,

1 '- [4- (4-phenoxyphenyl) -4-oxobutyl] spiro [isoquinolin-1- (2H) -4'-piperidin-3- (4H) -one] hydrochloride,

1 '- [4- (4-bromophenyl) -4-oxobutyl] spiro [isoquinolin-1- (2H) -4'-piperidin-3- (4H) -one],

1 '- [4- (4-chlorophenyl) -4-oxobutyl] spiro [isoquinolin-1- (2H) -4'-piperidin-3- (4H) -one] hydrochloride,

1 '- [2 - [(1,1'-biphenyl) -3-yl] -2-oxoethyl] spiro [isoquinolin-1- (2H) -4'-piperidin-3- (4H) -one] hydrochloride,

1 '- [3 - [(1,1'-biphenyl) -4-yl] -3-oxopropyl] spiro [isoquinolin-1- (2H) -4'-piperidin-3- (4H) -one] hydrochloride,

1 '- [4- (1,1'-biphenyl) -4-yl] -4-oxobutyl] spiro [isoquinolin-1- (2H) -4'-piperidin-3- (4H) -one] hydrochloride,

1 '- [2- (1,1'-biphenyl) -4-yl] -2-hydroxyethyl] spiro [isoquinolin-1- (2H) -4'-piperidin-3- (4H) -one] hydrochloride.

Reference: see US Patent No. 6348472

Triazine derivatives of Y receptor antagonists, such as:

N1 - {[4 - ({[4- (isopropylamino) -6- (methylamino) -1,3,5-triazin-2-yl] amino} methyl) cyclohexyl] methyl} -1-naphthalenesulfonamide,

N1- [4 - ([4- (ethylamino) -6- (isopropylamino) -1,3,5-triazin-2-yl] aminomethyl) cyclohexyl] methyl-1-naphthalenesulfonamide) -6- (isopropylamino) -1, 3,5-triazin-2-yl] amino} methyl) cyclohexyl] methyl} -1-naphthalenesulfenamide

N1 - {[4 - ({[4,6-di (isopropylamino) -1,3,5-triazin-2-yl] amino} methyl) cyclohexyl] methyl} -1-naphthalenesulfonamide,

N1- [4 - ([4- (isopropylamino) -6- (propylamino) -1,3,5-triazin-2-yl] aminomethyl) cyclohexyl-3-methyl-1-naphthalenesulfonamide,

N1- [4 - ([4- (butylamino) -6- (isopropylamino) -1,3,5-triazin-2-yl] aminomethyl) cyclohexyl] methyl-1-naphthalenesulfonamide,

N1- [4 - ([4-cyclobutylamino) -6- (isopropylamino) -1,3,5-triazin-2-yl] aminomethyl) cyclohexyl] methyl-1-naphthalenesulfonamide,

N1- [4 - ([4- (cyclopropylamino) -6- (isopropylamino) -1,3,5-triazin-2-yl] aminomethyl) cyclohexyl] methyl-1-naphthalenesulfonamide,

N1- [4 - ([4- (isopropylamino) -6- (pentylamino) -1,3,5-triazin-2-yl] aminomethyl) cyclohexyl] methyl-1-naphthalenesulfonamide,

N1- [4 - ([4 - [(2-cyanoethyl) amino] -6- (isopropylamino) -1,3,5-triazin-2-yl] aminomethyl) cyclohexyl] methyl-1-naphthalenesulfonamide,

N1- [4 - ([4 - [(2-hydroxyethyl) amino] -6- (isopropylamino) -1,3,5-triazin-2-yl] aminomethyl) cyclohexyl] methyl-1-naphthalenesulfonamide,

N1- (4 - [(4- (isopropylamino) -6 - ((2-methoxyethyl) amino] -1,3,5-triazin-2-yl] amino) methyl] cyclohexylmethyl) -1-naphthalenesulfonamide,

N1- (4 - [(4- (isopropylamino) -6 - [(3-methoxypropyl) amino] -1,3,5-triazin-2-ylamino) methyl] cyclohexylmethyl) -1-naphthalenesulfonamide,

N1 - {[4 - ({[4 -} [2- (dimethylamino) ethyl] amino} -6- (isopropylamino) -1,3,5-triazin-2-yl] amino} methyl) cyclohexyl] methyl} - 1-naphthalenesulfonamide,

N1- [4 - ([4- [3- (1H-1-imidazolyl) propyl] amino-6- (isopropylamino) -1,3,5-triazin-2-yl] aminomethyl) cyclohexyl] methyl-1-naphthalenesulfonamide ,

N1 - ({4 - [({4- (isopropylamino) -6-1- (4-methoxyphenethyl) amino] -1,3,5- [triazin-2-yl} amino) methyl] cyclohexyl} methyl) -1 naphthalenesulfonamide,

N1 - {[4 - ({[4- (dimethylamino) -6- (isopropylamino) -1,3,5-triazin-2-yl] amino} methyl) cyclohexyl] methyl} -1-naphthalenesulfonamide,

N1- [4 - ([4- [ethyl (methyl) amino]] -6- (isopropylamino) -1,3,5-triazin-2-yl] aminomethyl) cyclohexyl] methyl-1-naphthalenesulfonamide,

N1- [4 - ([4- (diethylamino) -6- (isopropylamino) -1,3,5-triazin-2-yl] aminomethyl) cyclohexylmethyl-1-naphthalenesulfonamide,

N1- [4 - ([4- (isopropylamino) -6-tetrahydro-1H-1-pyrrolyl-1,3,5-triazin-2-yl] aminomethyl) cyclohexyl] methyl-1-naphthalenesulfonamide,

N1- (4 - [(4- (isopropylamino) -6 - [(2S) -2- (methoxymethyl) tetrahydro-1H-1-pyrrolyl] -1,3,5-triazin-2-ylamino) methyl] cyclohexyl methyl ) -1-naphthalenesulfonamide,

N1 - {[4 - ({[4- (isopropylamino) -6-piperidino-1,3,5-triazin-2-yl] amino} methyl) cyclohexyl] methyl} -1-naphthalenesulfonamide,

N1- [4 - ([4- (isopropylamino) -6- (2-methylpiperidino) -1,3,5-triazin-2-yl] aminomethyl) cyclohexyl] methyl-1-naphthalenesulfonamide,

N1- [4 - ([4- (isopropylamino) -6-morpholino-1,3,5-triazin-2-yl] aminomethyl) cyclohexyl] methyl-1-naphthalenesulfonamide,

N1 - {[4 - ({[4 - [(2R, 6S) -2,6-dimethyl-1,4-oxazinan-4-yl] -6- (isopropylamino) -1,3,5-triazin-2 -yl] amino} methyl) cyclohexyl] methyl} -1-naphthalenesulfonamide,

N1- [4 - ([4 - [(2-hydroxyethyl) (methyl) amino] -6- (isopropylamino) -1,3,5-triazin-2-yl] aminomethyl) cyclohexyl] methyl-1-naphthalenesulfonamide,

N1 - {[4 - ({[4- (4-acetylpiperazino) -6- (isopropylamino) -1,3,5-triazin-2-yl] amino} methyl) cyclohexyl] methyl} -1-naphthalenesulfonamide,

N1 - {[4 - ({[4- (isopropylamino) -6- (4-isopropylpiperazino) -1,3,5-triazin-2-yl] amino} methyl) cyclohexyl] methyl} -1-naphthalenesulfonamide,

N1- [4 - ([4,6-di (ethylamino) -1,3,5-triazin-2-yl] aminomethyl) cyclohexyl] methyl-4- (tert-butyl) -1-benzenesulfonamide,

N1- [4 - ([4,6-di (ethylamino) -1,3,5-triazin-2-yl] aminomethyl) cyclohexyl] methyl-4-fluoro-1-benzenesulfonamide,

N1- [4 - ([4,6-di (ethylamino) -1,3,5-triazin-2-yl] aminomethyl) cyclohexyl] methyl-2-methoxy-5-methyl-1-benzenesulfonamide,

N1- [4 - ([4,6-di (ethylamino) -1,3,5-triazin-2-yl] aminomethyl) cyclohexyl] methyl-2-fluoro-1-benzenesulfonamide,

N1- [4 - ([4,6-di (ethylamino) -1,3,5-triazin-2-yl] aminomethyl) cyclohexyl] methyl-2-methyl-1-benzenesulfonamide,

N3- [4 - ([4,6-di (ethylamino) -1,3,5-triazin-2-yl] aminomethyl) cyclohexyl] methyl-3-pyridinesulfonamide,

N1- [4 - ([4,6-di (ethylamino) -1,3,5-triazin-2-yl] aminomethyl) cyclohexyl] methyl-4-methoxy-1-benzenesulfonamide,

N5- [4 - ([4,6-di (ethylamino) -1,3,5-triazin-2-yl] aminomethyl) cyclohexyl] methyl-2,4-dimethyl-1,3-oxazole-5-sulfonamide,

N2- [4 - ([4,6-di (ethylamino) -1,3,5-triazin-2-yl] aminomethyl) cyclohexyl] methyl-2-thiophenesulfonamide,

N4- [4 - ([4,6-di (ethylamino) -1,3,5-triazin-2-yl] aminomethyl) cyclohexyl] methyl-1-methyl-1H-4-imidazolosulfonamide,

N1- [4 - ([4,6-di (ethylamino) -1,3,5-triazin-2-yl] aminomethyl) cyclohexyl] methyl-4-methyl-1-benzenesulfonamide,

N5- [4 - ([4,6-di (ethylamino) -1,3,5-triazin-2-yl] aminomethyl) cyclohexyl] methyl-2,1,3-benzothiadiazole-5-sulfonamide,

N8- [4 - ([4,6-di (ethylamino) -1,3,5-triazin-2-yl] aminomethyl) cyclohexyl] methyl-8-quinoline sulfonamide-yl] aminomethyl) cyclohexyl] methylmethane sulfonamide,

N1- [4 - ([4- (isopropylamino) -6-tetrahydro-1H-1-pyrpolylyl-1,3,5-triazin-2-yl] aminomethyl) cyclohexyl] methyl-1-pyrrolidine sulfonamide,

N4- [4 - ([4- (isopropylamino) -6-morpholin-1,3,5-thiazin-2-yl] aminomethyl) cyclohexyl] methyl-4-morpholinesulfonamide,

N1- [4 - ([4- (isopropylamino) -6-piperidino-1,3,5-triazin-2-yl] aminomethyl) cyclohexyl] methyl-1-piperidinesulfonamide,

N1 - [(4 - [(4,6-ditetrahydro-1H-1-pyrrolyl-1,3,5-triazin-2-yl) amino] methylcyclohexyl) methyl] -4- (tert-butyl) -1-benzenesulfonamide ,

N-cyclopropyl-N '- [4 - ([4- (cyclopropylamino) -6- (isopropylamino) -1,3,5-triazin-2-yl] aminomethyl) cyclohexyl] methylsulfamide,

N '- [4 - ([4- (cyclopropylamino) -6- (isopropylamino) -1,3,5-triazin-2-yl] aminomethyl) cyclohexyl] methyl-N, N-dimethylsulfamide,

N1 - {[4 - ({[4-chloro-6- (isopropylamino) -1,3,5-triazin-2-yl] amino} methyl) cyclohexyl] methyl} -1-naphthalenesulfonamide,

N '- [(4 - [(4,6-dimorpholino-1,3,5-triazin-2-yl) amino] methylcyclohexyl) methyl] -N, N- [dimethylsulfamide,

N1- [4 - ([4-chloro-6- (isopropylamino) -1,3,5-triazin-2-yl] aminomethyl) cyclohexyl] methyl-4- (tert-butyl) -1-benzenesulfonamide,

N1- [4 - ([4- (cyclopropylamino) -6-tetrahydro-1H-1-pyrrolyl-1,3,5-triazin-2-yl] aminomethyl) cyclohexyl] methyl-4-fluoro-1-benzenesulfonamide,

N '- ((4 - (((4,6-dichloro-1,3,5-triazin-2-yl) amino) methyl) cyclohexyl) methyl) -N, N-dimethyl sulfamide,

N1 - [(4 - [(4,6-ditetrahydro-1H-1-pyrrolyl-1,3,5-triazin-2-yl) amino] methylcyclohexyl) methyl] -2-methoxy-5-methyl-1-benzenesulfonamide ,

N1- [4 - ([4- (cyclopropylamino) -6- (2-pyridyl) -1,3,5-triazin-2-yl] aminomethyl) cyclohexyl] methyl-4-fluoro-1-benzenesulfonamide,

N1- [4- (aminomethyl) cyclohexyl] methyl-4-fluoro-1-benzenesulfonamide,

N2, N4-diethyl-N6- [5- (1H-1-pyrazolyl) pentyl] -1,3,5-triazine-2,4,6-triamine

N2, N4-diethyl-N6- [3- (1H-1-imidazolyl) propyl] -1,3,5-triazine-2,4,6-triamine

N2, N4-diethyl-N6- (2-pyridylmethyl) -1,3,5-triazine-2,4,6-triamine

Reference: US Patent No. 6340683

Tricyclic compounds of Y receptor antagonists, such as:

trans-N2- (4-dimethylaminosulfonylaminomethyl) cyclohexyl-9-fluoro-5,6-dihydro-4H-benzo [6,7] cyclohepta [d] [1,3] [thiazole-2-amine;

1-aza-9-fluoro-4,5-dihydro-2- {5- (dimethylaminosulfonyl-amino) pentyl} amino-3-thia-benzo [e] azulene;

1-aza-9-fluoro-2- (5- (2-fluorophenyl) sulfonylamino) pentylamino-4,5-dihydro-3-thiabenzo [e] azulene;

1-aza-9-fluoro-4,5-dihydro-2- (5- (1-naphthyl) sulfonylamino) pentylamino-3-thiabenzo [e] azulene;

1-aza-9-fluoro-4,5-dihydro-2- (4- (methanesulfonylamino) butyl) amino-3-thiabenzo [e] azulene;

1-aza-9-fluoro-4,5-dihydro-2- (4- (dimethylaminosulfonylamino) butyl) amino-3-thiabenzo [e] azulene;

1-aza-9-fluoro-2- (4- (2-fluorophenyl) sulfonylamino) butylamino-4,5-dihydro-3-thiabenzo [e] azulene-3-thiabenzo [e] azulene;

1-aza-9-fluoro-4,5-dihydro-2- (4 - ((2 (S) -methoxymethyl) pyrrolidin-1-yl) sulfonyl) phenylamino-3-thiabenzo [e] azulene;

1-aza-9-fluoro-4,5-dihydro-2- (5- (methylsulfonylamino) pentyl) amino-3-thiabenzo [e] azulene;

trans-1-aza-9-fluoro-4,5-dihydro-2- (4- (methylsulfonylaminomethyl) cyclohexyl) amino-3-thiabenzo [e] azulene;

1-aza-9-fluoro-4,5-dihydro-2- (5- (2,4-difluorophenyl) sulfonylamino) pentylamino-3-thiabenzo [e] azulene;

1-aza-9-fluoro-4,5-dihydro-2- (5-isopropylsulfonylamino) pentylamino-3-thiabenzo [e] azulene;

1-aza-9-fluoro-4,5-dihydro-2- (5- (diethylaminosulfonylamino) pentyl) amino-3-thiabenzo [e] azulene;

1-aza-9-fluoro-4,5-dihydro-2- (5- (2-methoxy-5-methylphenyl) sulfonylamino) pentylamino-3-thiabenzo [e] azulene;

1-aza-2- (5-benzylsulfonylamino) pentylamino-9-fluoro-4,5-dihydro-3-thiabenzo [e] azulene;

1-aza-2- (5- (3,4-difluorophenyl) sulfonylamino) pentylamino-9-fluoro-4,5-dihydro-3-thiabenzo [e] azulene;

1-aza-9-fluoro-4,5-dihydro-2- (5- (4-methoxyphenyl) sulfonylamino) pentylamino-3-thiabenzo [e] azulene;

1-aza-9-fluoro-4,5-dihydro-2- (5- (2-thienyl) sulfonylamino) pentylamino-3-thiabenzo [e] azulene;

1-aza-9-fluoro-2- (5- (2-trifluoroethyl) sulfonylamino) pentylamino-4,5-dihydro-3-thiabenzo [e] azulene;

1-aza-9-fluoro-2- (5-ethylsulfonylamino) pentylamino-4,5-dihydro-3-thiabenzo [e] azulene;

1-aza-2- (4-diethylaminosulfonylamino) butylamino-9-fluoro-4,5-dihydro-3-thiabenzo [e] azulene;

1-aza-9-fluoro-4,5-dihydro-2- (5- (1-methylimidazol-4-yl) sulfonylamino) pentylamino-3-thiabenzo [e] azulene;

1-aza-9-fluoro-4,5-dihydro-2- (5- (3,5-dimethylisoxazol-4-yl) sulfonyl-amino) pentylamino-3-thiabenzo [e] azulene;

1-aza-9-fluoro-4,5-dihydro-2- (5-aminosulfonylamino) pentylamino-3-thiabenzo [e] azulene;

trans-1-aza-9-fluoro-2- (4- (2-fluorophenyl) sulfonylaminomethyl) cyclohexyl-amino-4,5-dihydro-3-thiabenzo [e] azulene;

trans-1-aza-9-fluoro-4,5-dihydro-2- {4- (4-methoxyphenyl) sulfonylaminomethyl} cyclohexylamino-3-thiabenzo [e] azulene;

trans-N2- (4- (2,6-difluorophenylsulfonyl) aminomethyl) cyclohexyl-9-fluoro-5,6-dihydro-4H-benzo [6,7] cyclohepta- [d] [1,3] thiazole-2 -amine;

trans-1-aza-2- {4-benzylsulfonylaminomethyl} cyclohexylamino-9-fluoro-4,5-dihydro-3-thiabenzo [e] azulene;

trans-N2- (4- (2-thienylsulfonyl) aminomethyl) cyclohexyl-9-fluoro-5,6-di-hydro-4H-benzo [6,7] cyclohepta [d] [1,3] thiazole-2-amine ;

trans-N2- (4-ethylsulfonylaminomethyl) cyclohexyl-9-fluoro-5,6-dihydro-4H-benzo [6,7] cyclohepta [d] [1,3] thiazole-2-amine;

trans-1-aza-9-fluoro-4,5-dihydro-2- {4- (1-methylimidazolyl-4-yl) sulfonyl-aminomethyl} cyclohexylamino-3-thia-benzo [e] azulene;

trans-1-aza-9-fluoro-4,5-dihydro-2- {4- (3,5-dimethylisoxazol-4-yl) sulfonylaminomethyl} cyclohexylamino-3-thiabenzo [e] azulene) cyclohexyl amino 3-thiabenzo [e] azulene;

trans-1-aza-9-fluoro-4,5-dihydro-2- (4-diethylaminosulfonylamino) cyclohexylamino-3-thiabenzo [e] azulene;

trans-1-aza-9-fluoro-4,5-dihydro-2- (4- (4-methoxyphenyl) sulfonylamino) cyclohexylamino-3-thiabenzo [e] azulene;

trans-1-aza-9-fluoro-4,5-dihydro-2- (4- (2-thienyl) sulfonylamino) cyclohexylamino-3-thiabenzo [e] azulene;

trans-1-aza-9-fluoro-4,5-dihydro-2- (4- (2,2,2-trifluoro-ethyl) sulfonylamino) cyclohexylamino-3-thiabenzo [e] azulene;

1-aza-9-fluoro-4,5-dihydro-2- (4- (2,2,2-trifluoroethyl) sulfonylamino) butyl-amino-3-thiabenzo [e] azulene;

trans-1-aza-9-fluoro-2- {4- (3,4-difluorophenyl) sulfonyl-aminomethyl} cyclohexylamino-4,5-dihydro-3-thiabenzo [e] azulene;

trans-1-aza-9-fluoro-2- {4-trifluoromethylsulfonylaminomethyl} cyclohexamino-4,5-dihydro-3-thiabenzo [e] azulene;

trans-1-aza-9-fluoro-2- {4- (2-fluoro) phenylsulfonylamino} cyclohexylmethylamino-4,5-dihydro-3-thiabenzo [e] azulene;

trans-N2- (4-methylsulfonylamino) cyclohexylmethyl-9-fluoro-5,6-dihydro-4H-benzo [6,7] cyclohepta [d] [1,3] thiazole-2-amine: Trans-N2- ( 4-amino) cyclohexylmethyl-9-fluoro-5,6-dihydro-4H-benzo [6,7] cyclohepta [d] [1,3] thiazole-2-amine dihydrochloride;

trans-N2- (4-aminosulfonylamino) cyclohexylmethyl-9-fluoro-5,6-dihydro-4H-benzo [6,7] cyclohepta [d] [1,3] thiazole-2-amine;

trans-N2- (4-amino) cyclohexylmethyl-9-fluoro-5,6-dihydro-4H-benzo [6,7] cyclohepta [d] [1,3] thiazole-2-amine;

trans-N2- (4-aminosulfonylamino) cyclohexylmethyl-9-fluoro-5,6-dihydro-4H-benzo [6,7] cyclohepta [d] [1,3] thiazole-2-amine;

9-fluoro-5,6-dihydro-4H-benzo [6,7] cyclohepta [d] [1,3] thiazole-2-amine:

6-bromo-3-fluoro-6,7,8,9-tetrahydro-5H-benzo [a] cyclohepten-5-one;

N1- (9-fluoro-5,6-dihydro-4H-benzo [6,7] cyclohepta [d] [1,3] thiazol-2-yl) -5-bromopentanamide;

[1-5 - [(9-fluoro-5,6-dihydro-4H-benzene [6,7] cyclohepta [d] [1,3] -thiazol-2-yl) amino] -5-oxopentyl-1, 2-triazadiene-2-yum;

N1- (9-fluoro-5,6-dihydro-4H-benzo [6,7] cyclohepta [d] [1,3] thiazol-2-yl) -5-aminopentanamide;

N1- (9-fluoro-5,6-dihydro-4H-benzo [6,7] cyclohepta [d] [1,3] thiazol-2-yl) -5 - [(methylsulfonyl) amino] pentanamide;

trans-N2- (4-aminosulfonylaminomethyl) cyclohexyl-4,5-dihydro-benzo [2,3] oxepino [4,5-d] [1,3] thiazole-2-amine;

trans-N2- (4-methylsulfonylaminomethyl) cyclohexyl-4,5-dihydro-benzo [2,3] oxepino [4,5-b] [1,3] thiazole-2-amine;

trans-1-aza-4,5-dihydro-2- {4- (2-methoxy-5-methyl) phenyl-sulfonylamino-methyl} cyclohexylamino-6-oxa-3-thiabenzo [e] azulene;

N1- (9-fluoro-5,6-dihydro-4H-benzo [6,7] cyclohepta [d] [1,3] -thiazol-2-yl) -5 - [(2-methoxy-5-methylphenyl) sulfonyl] aminopentanamide;

N1- (9-fluoro-5,6-dihydro-4H-benzo [6,7] cyclohepta [d] [1,3] thiazol-2-yl) -5-aminopentanamide;

trans-N2- (4-methylsulfonylamino) cyclohexylmethyl-4,5-dihydro-benzo [2,3] oxepino [4,5-d] [1,3] thiazole-2-amine;

trans-1-aza-4,5-dihydro-2- {4- (2-methoxy-5-methylphenyl) sulfonylamino} cyclohexylmethylamino-6-oxa-3-thiabenzo [e] azulene;

trans-N2- (4-ethylsulfonylamino) cyclohexylmethyl-9-fluoro-5,6-dihydro-4H-benzo [6,7] cyclohepta [d] [1,3] thiazol-2-amine;

trans-1-aza-9-fluoro-4,5-dihydro-2- {4-isopropylsulfonylamino} cyclohexylmethylamino-3-thiabenzo [e] azulene;

trans-1-aza-9-fluoro-4,5-dihydro-2- (4- (3-pyridylsulfonylamino) cyclohexyl) amino-3-thiabenzo [e] azulene;

1-aza-9-fluoro-4,5-dihydro-2- (5- (3-pyridyl) sulfonylamino) pentylamino-3-thiabenzo [e] azulene;

1-aza-9-fluoro-4,5-dihydro-2- (4- (3-pyridyl) sulfonylamino) butylamino-3-thiabenzo [e] azulene;

1-aza-9-fluoro-4,5-dihydro-2- {2- (2-methylsulfonylamino) ethoxy} ethyl-amino-3-thiabenzo [e] azulene;

1-aza-9-fluoro-4,5-dihydro-2- {2- [2- (2-methoxy-5-methylphenyl) sulfonylamino] ethoxy} ethylamino-3-thiabenzo [e] azulene;

trans-1-aza-9-fluoro-4,5-dihydro-2- (4- (3-pyridyl) sulfonylaminomethyl) cyclohexylamino-3-thiabenzo [e] azulene;

trans-N2- (4-ethylsulfonylamino) cyclohexylmethyl-8-methoxy-4,5-dihydro-benzo [2,3] oxepino [4,5-c1] [[1,3] thiazole-2-amine;

trans-1-aza-4,5-dihydro-8-methoxy-2- {4-methylsulfonyl-amino) cyclohexylmethylamino-6-oxa-3-thiabenzo [e] azulene;

trans-1-aza-9-fluoro-4,5-dihydro-2 - [{4- (3-pyridyl) sulfonylamino} cyclohexylmethylamino-3-thiabenzo [e] azulene;

trans-1-aza-4,5-dihydro-9-methoxy-2- {4-methylsulfonylamino} cyclohexylmethylamino-6-oxa-3-thiabenzo [e] azulene;

trans-N2- (4-ethylsulfonylamino) cyclohexylmethyl-9-methoxy-4,5-dihydro-benzo [2,3] oxepino [4,5-d] [1,3] thiazole-2-amine;

trans-N2- (4-methylsulfonylamino) cyclohexylmethyl-7-methoxy-4,5-dihydro-benzo [2,3] oxepino [4,5-d] [1,3] thiazole-2-amine hydrochloride;

trans-1-aza-4,5-dihydro-7-methoxy-2- {4-dimethylaminosulfonylamino} cyclohexylmethylamino-6-oxa-3-thiabenzo [e] azulene;

trans-N2- (4-dimethylphosphonylamino) cyclohexylmethyl-9-fluoro-5,6-dihydro-4H-benzo [6,7] cyclohepta [d] [1,3] thiazole-2-amine;

trans-N2- (4-ethoxycarbonylamino) cyclohexylmethyl-9-fluoro-5,6-dihydro-4H-benzo [6,7] cyclohepta [d] [1,3] thiazole-2-amine hydrochloride;

1-aza-9-fluoro-4,5-dihydro-2- (2- (2-isopropylsulfonylamino) ethoxy) ethyl-amino-3-thiabenzo [e] azulene;

2- (4-methylsulfonylaminomethyl) cyclohexylamino-4H-chromeno [4,3-d] thiazole;

trans-1-aza-4,5-dihydro-8-methoxy-2- (4-methylsulfonylamino) cyclohexylmethylamino-3-thiabenzo [e] azulene;

trans-1-aza-4,5-dihydro-8-methoxy-2- (4-methylsulfonylaminomethyl) cyclohexylamino-3-thiabenzo [e] azulene;

trans-1-aza-4,5-dihydro-2- (4-isopropylsulfonylaminomethyl) cyclohexylamino-8-methoxy-3-thiabenzo [e] azulene;

trans-1-aza-4,5-dihydro-2- (4-methylsulfonylaminomethyl) cyclohexyl-amino-7-methoxy-3-thiabenzo [e] azulene;

trans-1-aza-4,5-dihydro-2- (4-ethylcarbonylaminomethyl) cyclohexylamino-9-fluoro-3-thiabenzo [e] azulene;

trans-1-aza-9-fluoro-4,5-dihydro-2- (4- (4-morpholinyl) sulfonylamino-methyl) cyclohexylamino-3-thiabenzo [e] azulene;

trans-1-aza-9-fluoro-4,5-dihydro-2- (4- (2-methoxy) ethoxy-carbonylamino-methyl) cyclohexylamino-3-thiabenzo [e] azulene 2-methoxyethyl-N- ( t4- (9-fluoro-5,6-dihydro-4H-benzo [6,7] cyclohepta [d] [1,3] thiazol-2-yl) amino] cyclohexyl} methyl) carbamate;

tert-butyl-N - [(4 - {[(benzoylamino) carbothoyl] amino} cyclohexyl) methyl] carbamate;

tert-butyl-N - ({4 - [(aminocarbothioyl) amino] cyclohexyl} methyl)] carbamate;

6-bromo-3-fluoro-6,7,8,9-tetrahydro-5H-benzo [a] cyclohepten-5-one;

tert-butyl-N - ({4 - [(9-fluoro-5,6-dihydro-4H-benzo [6,7] cyclohepta- [D] [1,3] thiazol-2-yl) amino] cyclohexyl} methyl) carbamate;

trans-N2 - [[4- (aminomethyl) cyclohexyl] -9-fluoro-5,6-dihydro-4H-benzo [6,7] cyclohepta [d] [1,3] thiazole-2-amine;

trans-1-aza-9-fluoro-4,5-dihydro-2- (4- (2-methoxy) ethoxycarbonylamino-methyl) cyclohexylamino-3-thiabenzo [e] azulene 2-methoxyethyl N - [({4 - [(9-fluoro-5,6-dihydro-4H-benzo [6,7] cyclohepta [d] [1,3] thiazol-2-yl) amino] cyclohexyl} methyl)] carbamate;

trans-N2- (4- (1-morpholinylsulfonylaminomethyl)] cyclohexyl-8-methoxy-5,6-dihydro-4H-benzo [6,7] cyclohepta [d] [1,3] thiazole-2-amine hydrochloride;

3 - ({4 - [(9-fluoro-5,6-dihydro-4H-benzene [6,7] cyclohepta [d] [1,3] thiazol-2-yl) amino] cyclohexyl} methyl) - 1 3-oxazolan-2one;

2-chloroethyl-N - ({4 - [(9-fluoro-5,6-dihydro-4H-benzo [6,7] cyclohepta [d] [1,3] thiazol-2-yl) amino] cyclohexyl} methyl ) carbamate;

3 - ({4 - [(9-fluoro-5,6-dihydro-4H-benzo [6,7] cyclohepta [d] [1,3] thiazol-2-yl) amino] cyclohexyl} methyl) -1, 3-oxazolan-2one;

N - ({4 - [(9-fluoro-5,6-dihydro-4H-benzo [6,7] cyclohepta- [D] [1,3] thiazol-2-yl) amino] cyclohexyl} methyl) -2 methoxyacetamide;

N1 - ({4 - [(9-fluoro-5,6-dihydro-4H-benzo [6,7] -cyclohepta-D] [1,3] thiazol-2-yl) amino] cyclohexyl} methyl) acetamide;

trans-1-aza-9-fluoro-4,5-dihydro-2- (4- (N-propylformamido) methyl) cyclohexamino-3-thiabenzo [e] azulene;

trans-1-aza-9-fluoro-4,5-dihydro-2- (4- (N-isopropyl formamido) methyl) cyclohexylamino-3-thiabenzo [e] azulene;

N1- {4 - [(4,5-dihydrobenzo [2,3] oxepino [4,5-d] [1,3] thiazol-2-ylamino) methyl] cyclohexyl} -2-methoxyacetamide;

benzyl N- (4 - {[(aminocarbothioyl) amino] methyl} cyclohexyl) carbamate;

benzyl-N- {4 - [(4,5-dihydrobenzo [2,3] oxepino [4,5-d] [1,3] -thiazol-2-yl-amino) methyl] cyclohexyl} carbamate;

N2 - [(4-aminocyclohexyl)] methyl] -4,5-dihydrobenzo [2,3] oxepino [4,5-d] [1,3] thiazole-2-amine;

N - {[4- (4,5-dihydrobenzo [2,3] oxepino [4,5-d] [1,3] thiazol-2-ylamino) cyclohexyl] methyl} -N-propylformamide;

N1 - {[[4- (4,5-dihydrobenzo [2,3] oxepino [4,5-d] [1,3] thiazol-2-ylamino) cyclohexyl] methyl} propanamide;

N2- {4 - [(propylamino)] methyl] cyclohexyl} -4,5-dihydrobenzo- [2,3] oxepino- [4,5-d] [1,3] thiazole-2-amine;

N - [{[4- (4,5-dihydrobenzo [2,3] oxepino [4,5-d] [1,3] thiazol-2-ylamino) cyclohexyl] methyl} -N-propylformamide;

N- {4 - [(4,5-dihydrobenzo [2,3] oxepino [4,5-d] [[1,3] thiazol-2-ylamino) methyl] cyclohexyl} -N- (2-methoxyethyl) formamide ;

N2 - ({4 - [(2-methoxyethyl) amino] cyclohexyl} methyl) -4,5-dihydrobenzo [2,3] oxepino [4,5-d] [1,3] thiazole-2-amine;

N- {4 - [(4,5-dihydrobenzo [2,3] oxepino [4,5-d] [1,3] thiazol-2-ylamino) methyl] cyclohexyl} -N- (2-methoxyethyl) formamide;

trans-1-aza-2- (4- (n- (ethyl) formamido) cyclohexyl) methyl-amino-4,5-dihydro-6-oxa-3-thiabenzo [e] azulene;

trans-2- (4-acetamido) cyclohexylmethylamino-1-aza-4,5-dihydro-6-oxa-3-thia-benzo [e] azulene;

benzyl N- [4 - {[(benzoylamino) carbothoyl] amino} methyl) cyclohexyl] carbamate;

benzyl N- (4 - {[(aminocarbothioyl) amino] methyl} cyclohexyl) carbamate;

benzyl-N- {4 - [(4,5-dihydrobenzo [2,3] oxepino [4,5-d] [1,3] -thiazol-2-yl-amino) methyl] cyclohexyl} carbamate;

N2 - [(4-aminocyclohexyl) methyl] -4,5-dihydrobenzo [2,3] -oxepino- [4,5-d] [1,3] thiazol-2-amine;

N1- {4 - [(4,5-dihydrobenzo [2,3] oxepino [4,5-d] [1,3] thiazol-2-ylamino) methyl] cyclohexyl} acetamide;

N2- [4- (ethylamino) cyclohexyl] methyl} -4,5-dihydrobenzo- [2,3] oxepino [4,5-d] [1,3] thiazol-2-amine;

N- {4 - [(4,5-dihydrobenzo [2,3] oxepino [4,5-d] [1,3] thiazol-2-ylamino) methyl] cyclohexyl} -N-ethylformamide;

N- (4 - [(4,5-dihydrobenzo [2,3] oxepino [4,5-d] [1,3] thiazol-2-ylamino) methyl] cyclohexyl} -N-propylformamide;

N2 - {[4- (propylamino) cyclohexyl] methyl} -4,5-dihydrobenzo- [2,3] oxepino [4,5-d] [1,3] thiazole-2-amine;

N- {4 - [(4,5-dihydrobenzo [2,3] oxepino [4,5-d] [1,3] thiazol-2-ylamino) methyl] cyclohexyl} -N-propylformamide;

N1- {4 - [(9-fluoro-5,6-dihydro-4H-benzo [6,7] cyclohepta [d] [1,3] thiazol-2-yl) amino] benzyl} -2-methoxyacetamide;

N- {4 - [(9-fluoro-5,6-dihydro-4H-benzo [6,7] cyclohepta [d] [1,3] thiazol-2-yl) amino] benzyl} methanesulfonamide;

N2- [4- (aminomethyl) phenyl] -9-fluoro-5,6-dihydro-4H-benzo [6,7] cyclohepta [d] [1,3] thiazole-2-amine.

Reference: US Patent No. 6225330

Bicyclic compounds of Y receptor antagonists, such as:

2- (5-diethylaminosulfonylamino) pentylamino-4- (2-pyridyl) thiazole hydrochloride

4- (2-pyridyl) -2- (5- (2-thienyl) sulfonylaminopentyl) aminothiazole hydrochloride

2- (5- (2-fluorophenyl) sulfonylamino) pentylamino-4- (2-pyridyl) thiazole hydrochloride

2- (5- (4-methoxyphenyl) sulfonylamino) pentylamino-4- (2-pyridyl) thiazole hydrochloride

2- (5- (3,5-dimethylisoxazol-4-yl) sulfonylamino) pentylamino-4- (2-pyridyl) thiazole hydrochloride

2- (5- (3,4-difluorophenyl) sulfonylamino) pentylamino-4- (2-pyridyl) thiazole hydrochloride

2- (5- (2-methoxy-5-methylphenyl) sulfonylamino) pentylamino-4- (2-pyridyl) thiazole hydrochloride

2- (5- (benzylsulfonylamino) pentylamino-4- (2-pyridyl) thiazole hydrochloride

2- (5- (ethylsulfonylamino) pentyl) amino-4- (2-pyridyl) thiazole hydrochloride

2- (5- (trifluoromethylsulfonylamino) pentyl) amino-4- (2-pyridyl) thiazole hydrochloride

2- (5- (aminosulfonylamino) pentyl) amino-4- (2-pyridyl) thiazole hydrochloride

2- (5- (2-fluorophenyl) sulfonylamino) pentylamino-4- (3-pyridyl) thiazole hydrochloride

2- (5- (3,5-dimethylisoxazol-4-yl) sulfonylamino) pentylamino-4- (3-pyridyl) thiazole hydrochloride

2- (5- (2-methoxy-5-methyl) phenylsulfonylamino) pentylamino-4- (3-pyridyl) thiazole hydrochloride

2- (5- (2-fluoro) phenylsulfonylamino) pentylamino-4- (4-pyridyl) thiazole hydrochloride

2- (5- (3,5-dimethylisoxazol-4-yl) sulfonylamino) pentylamino-4- (4-pyridyl) thiazole hydrochloride

2- (5- (2-methoxy-5-methyl) phenylsulfonylamino) pentylamino-4- (4-pyridyl) thiazole hydrochloride

N- {5 - [(4-benzo [b] thiophen-2-yl-1,3-thiazol-2-yl) amino] pentyl} -2-methoxy-5-methyl-1-benzenesulfonamide

N1- (5 - {[4- (5- [lor-3-methylbenzo [b] thiophen-2-yl) -1,3-thiazol-2-yl] amino} pentyl) -2-methoxy-5-methyl -1-benzene-sulfonamide

N1- (4 - {[4- (5-phenyl-3-isoxazolyl) -1,3-thiazol-2-yl) amino} -pentyl) -2-methoxy-5-methyl-1-benzenesulfonamide

N1- (5 - {[4- (3-thienyl) -1,3-thiazol-2-yl] amino} pentyl) -2-methoxy-5-methyl-1-benzenesulfonamide

N1- [5 - ({4- [1- (phenylsulfonyl) -1H-3-pyrrolyl-1,3-thiazol-2-yl} amino) pentyl] -2-methoxy-5-methyl-1-benzenesulfonamide

trans-N8 - [(4 - {[4- (3-Phenyl-5-isoxazoyl) -1,3-thiazol-2-yl] amino} cyclohexyl) methyl] -8-quinoline sulfonamide

N, N-dimethyl-N '- (5 - {[4- (3-thienyl) -1,3-thiazol-2-yl] amino} pentyl) sulfamide

trans-2- (4- (2-methoxy-5-methylphenyl) sulfonylamino) cyclohexylmethyl-amino-4- (2-pyridyl) thiazole dihydrochloride

trans-2- (4- (2-fluorophenyl) sulfonylamino) cyclohexylmethyl-amino-4- (2-pyridyl) thiazole dihydrochloride

trans-2- (4- (3,5-dimethyl-4-isoxazoyl) sulfonylamino) cyclohexylmethyl-amino-4- (2-pyridyl) thiazole dihydrochloride

trans-2- (4- (2-fluorophenyl) sulfonylamino) cyclohexylmethyl-amino-4- (3-pyridyl) thiazole dihydrochloride

trans-2- (4- (2-methoxy-5-methylphenyl) sulfonylamino) cyclohexylmethyl-amino-4- (4-pyridyl) thiazole dihydrochloride

N1- (5- [4- (1,3-thiazol-2-yl) -1,3-thiazol-2-yl] aminopentyl) -2-methoxy-5-methyl-1-benzenesulfonamide

trans-N1 - [(4- [4- (2,5-dimethyl-1,3-thiazol-4-yl) -1,3-thiazol-2-yl] aminocyclohexyl) methyl] -2-methoxy- 5-methyl-1-benzenesulfonamide

trans-N, N-dimethyl-N '- [(4- [4 - (- 1,3-thiazol-2-yl) -1,3-thiazol-2-yl] amino-cyclohexyl) methyl] sulfamide

N, N-dimethyl-N '- (5 - {[4- (2-thienyl) -1,3-thiazol-2-yl] amino} pentyl) sulfamide

N1- (5 - {[4- (2-thienyl) -1,3-thiazol-2-yl] amino} pentyl) -2-methoxy-5-methyl-1-benzenesulfonamide

N1- (5- [4- (2,5-dimethyl-1,3-thiazol-4-yl) -1,3-thiazol-2-yl] aminopentyl) -2-methoxy-5-methyl-1-benzenesulfonamide

N1- (5- [4- (2,5-dimethyl-1,3-thiazol-4-yl) -1,3-thiazol-2-yl] aminopentyl) -4-fluoro-1-benzenesulfonamide

N1- (5- [4- (1,3-thiazol-2-yl) -1,3-thiazol-2-yl] aminopentyl) -4-fluoro-1-benzene-sulfonamide

N '- (5- [4- (2,5-dimethyl-1,3-thiazol-4-yl) -1,3-thiazol-2-yl] aminopentyl) -N, N-dimethyl sulfamide

trans-N1 - [(4- [4- (2,6-dimethyl-1,3-thiazol-4-yl]) - 1,3-thiazol-2-yl] amino-cyclohexyl) methyl] -4-fluoro -1-benzene-sulfonamide

trans-N '- [(4- [4- (2,5-dimethyl-1,3-thiazol-4-yl) -1,3-thiazol-2-yl] amino-cyclohexyl) methyl] -N, N dimethyl sulfamide]

trans-N '- [4 - ([5- (2,5-dimethyl-1,3-thiazol-4-yl) -1,3-thiazol-2-yl] amino-methyl) cyclohexyl] methyl-N, N-dimethylsulfamide

trans-N4- [4 - ([4- (2,5-dimethyl-1,3-thiazol-4-yl) -1,3-thiazol-2-yl] amino-methyl) cyclohexyl] methyl-4-morpholine sulfonamide

trans-N- [4 - ([4- (2,5-dimethyl-1,3-thiazol-4-yl) -1,3-thiazol-2-yl] amino-methyl) cyclohexyl] -N- (2 methoxyethyl) formamide

trans-N- [4 - ([4- (2,5-dimethyl-1,3-thiazol-4-yl) -1,3-thiazol-2-yl] amino-methyl) cyclohexyl] -N-isopropylformamide

Reference: see US Patent No. 6218408

N-aralkylaminotetralin Y receptor antagonist, such as:

rac-cis-1- (phenylmethyl) -6-methoxy-N- (2- (3,4-dimethoxyphenyl) ethyl) -1,2,3,4-tetrahydro-2-naphthalene amine;

rac-cis-1- (phenylmethyl) -6-methoxy-N- (2- (3-indolyl) ethyl) -1,2,3,4-tetra-hydro-2-naphthalene amine hemifumarate;

rac-cis-1- (phenylmethyl) -N- (4-fluorophenylmethyl) -1,2,3,4-tetrahydro-2-naphtha-laminamine monohydrobromide;

rac-cis-1- (phenylmethyl) -N- (2-methoxyphenylmethyl) -1,2,3,4-tetrahydro-2-naphthalene amine;

rac-cis-1- (phenylmethyl) -N- (2-methoxyphenylmethyl) -1,2,3,4-tetrahydro-2-naphthalene amine monohydrobromide;

rac-cis-1- (4-fluorophenylmethyl) -N- (2-methoxyphenylmethyl) -1,2,3,4-tetrahydro-2-naphthalene amine monohydrobromide;

rac-trans-1- (4-fluorophenylmethyl) -N- (2-methoxyphenylmethyl) -1,2,3,4-tetrahydro-2-naphthalene amine monoxalate;

rac-cis-1- (phenylmethyl) -N- (4-fluorophenylmethyl) -1,2,3,4-tetrahydro-2-naphtha-laminamine monohydrobromide;

rac-cis-1- (phenylmethyl) -7-methoxy-N- (2-methoxyphenylmethyl) -1,2,3,4-tetra-hydro-2-naphthalene amine monohydrobromide;

rac-trans-1- (4-fluorophenylmethyl) -N- (2- (3-indolyl) ethyl) -1,2,3,4-tetrahydro-2-naphthalene amine monoxalate;

rac-cis-1- (phenylmethyl) -N- (2-methoxyphenyl-2-oxomethyl) -1,2,3,4-tetrahydro-2-naphthalene amine monohydrobromide;

rac-cis-1- (phenylmethyl) -7-methoxy-N- (2- (3-indolyl) ethyl) -1,2,3,4-tetrahydro-2-naphthalene amine 0.8 fumarate 0.8 methanol 0, 2 hydrate;

rac-trans-1- (phenylmethyl) -7-methoxy-N- (2 (3-indolyl) ethyl) -1,2,3,4-tetrahydro-2-naphthalene amine monoxalate;

rac-cis-1- (2-naphthylmethyl) -N- (2- (3-indolyl) ethyl) -1,2,3,4-tetrahydro-2-naphthalene amine hemifumarate methanol;

rac-trans-1- (2-naphthylmethyl) -N- (2- (3-indolyl) ethyl) -1,2,3,4-tetrahydro-2-naphthalene amine monoxalate;

rac-cis-1- (2-naphthylmethyl) -N- (2-methoxyphenylmethyl) -1,2,3,4-tetrahydro-2-naphthalene amine monohydrobromide;

rac-cis-1- (phenylmethyl) -N- (2-methoxyphenyl-2-oxoethyl) -1,2,3,4-tetrahydro-ro-2-naphthalene amine;

rac-cis-1- (4-fluorophenylmethyl) -N- (3-phenylpropyl) -1,2,3,4-tetrahydro-2-naphthalene amine monohydrobromide;

rac-cis-1- (3-pyridylmethyl) -N- (2- (3,4-dimethoxyphenyl) ethyl-1,2,3,4-tetrahydro-2-naphthalene amine monohydrobromide.

Reference: see US Patent No. 6201025

Amide derivative of receptor antagonist Y:

Reference: see US Patent No. 6048900

N-substituted aminotetralin Y receptor antagonists, such as:

rac- [1α, 2α (trans)] - N - [[[[[1,2,3,4-tetrahydro-6-methoxy-1- (phenylmethyl) -2-naphthalenyl] amino] methyl] 4-cyclohexyl] methyl] 2-naphthalenesulfonamide;

rac- [1α, 2α (trans)] - N - [[[[[[1,2,3,4-tetrahydro-6-methoxy-1- (phenylmethyl) -2-naphthalenyl] amino] -5-pentyl] 2 naphthalenesulfonamide;

rac- [1α, 2α (trans)] - N - [[[[[1,2,3,4-tetrahydro-6-methoxy-1- (3-pyridinyl-methyl) -2-naphthalenyl] amino] methyl] -4-cyclohexyl] methyl] 2-naphthalenesulfonamide;

rac- [1α, 2α (trans)] - N - [[[[[1,2,3,4-tetrahydro-6-fluoro-1- (phenylmethyl) -2-naphthalenyl] amino] methyl] -4-cyclohexyl ] methyl] 2-fluorobenzenesulfonamide;

rac- [1α, 2α (trans)] - N - [[[[[1,2,3,4-tetrahydro-6-fluoro-1-phenyl-2-naphthalenyl] amino] methyl] -4-cyclohexyl] methyl ] 2-naphthalenesulfonamide;

rac- [1α, 2α (trans)] - N - [[[[[1,2,3,4-tetrahydro-6-methoxy-1- (1-propen-3-yl) -2-naphthalenyl] amino] methyl] 4-cyclohexyl] methyl] benzenesulfonamide;

rac- [1α, 2α (trans)] - N - [[[[[1,2,3,4-tetrahydro-6-methoxy-1- (3-hydroxy-propyl) -2-naphthalenyl] amino] methyl] -4-cyclohexyl] methyl] benzenesulfonamide;

rac- [1α, 2α (trans)] - N - [[[[[1,2,3,4-tetrahydro-6-methoxy-1- (n-propyl) -2-naphthalenyl] amino] methyl] -4 β-cyclohexyl] methyl] benzenesulfonamide.

Reference: see US Patent No. 6140354

4-phenyl-1,4-dihydropyrimidine derivative of a receptor antagonist Y:

Reference: see US Patent No. 5889016

Piperidine derivative of dihydropyridine Y receptor antagonist:

Dimethyl ester

4-dihydro- [3 - [[[[[3- [4- (3-methoxyphenyl) -1-piperidinyl] propyl] amino] carbonyl] amino] phenyl] -2,6-dimethyl-3,5-pyridinedicarboxylic acid ;

Dimethyl ester

1,4-dihydro-4- [3 - [[[[3- [4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl] propyl] amino] carbonyl] amino] phenyl] -2,6- dimethyl-3,5-pyridinedicarboxylic acid;

Dimethyl ester

1,4-dihydro-4- [3 - [[[[3- [4- (2-methoxyphenyl) piperidin-1-yl] propyl] amino] carbonyl] amino] phenyl] -2,6-dimethyl-3, 5-pyridinedicarboxylic acid;

Dimethyl ester

1,4-dihydro-4- [3 - [[[[3- (4-phenylpiperidin-1-yl) propyl] amino] carbonyl] amino] phenyl] -2,6-dimethyl-3,5-pyridinedicarboxylic acid;

Dimethyl ester

1,4-dihydro-4- [3 - [[[[3- (4-hydroxy-4-phenylpiperidin-1-yl) propyl] amino] carbonyl] amino] phenyl] -2,6-dimethyl-3,5 -pyridinedicarboxylic acid;

Dimethyl ester

1,4-dihydro-2,6-dimethyl-4- [3 - [[[[3- [4- [3- (2-propynyloxy) phenyl] -1-piperidinyl] propyl] amino] carbonyl] amino] phenyl ] -3,5-pyridinedicarboxylic acid;

Dimethyl ester

1,4-dihydro-4- [3 - [[[[3- [4-cyano-4-phenylpiperidin-1-yl] propyl] amino] carbonyl] amino] phenyl] -2,6-dimethyl-3,5 -pyridinedicarboxylic acid;

Dimethyl ester

1,4-dihydro-4- [3 - [[[[3- [4- (3-hydroxyphenyl) piperidin-1-yl] propyl] amino] carbonyl] amino] phenyl] -2,6-dimethyl-3, 5-pyridinedicarboxylic acid;

Dimethyl ester

1,4-dihydro-4- [3 - [[[[3- [4-naphthalen-1-ylpiperidin-1-yl] propyl] amino] carbonyl] amino] phenyl] -2,6-dimethyl-3,5 -pyridinedicarboxylic acid;

Dimethyl ester

4- [3 - [[[[3- [4- (1,1'-biphenyl-3-yl) piperidin-1-yl] propyl] amino] carbonyl] amino] phenyl] -1,4-dihydro-2 6-dimethyl-3,5-pyridinedicarboxylic acid;

Dimethyl ester

1,4-dihydro-4- [3 - [[[[3- [4- (phenylmethyl) piperidin-1-yl] propyl] amino] carbonyl] amino] phenyl-2,6-dimethyl-3,5- pyridinedicarboxylic acid;

Dimethyl ester

4- [3 - [[[[3- (4-cyclohexyl-1-piperidinyl) propyl] amino] carbonyl] amino] phenyl] -1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid;

Dimethyl ester

1,4-dihydro-4- [3 - [[[[3- [4-hydroxy-4- (2-phenoxyphenyl) -1-piperidinyl] propyl] amino] carbonyl] amino] phenyl] -2,6-dimethyl -3,5-pyridinedicarboxylic acid;

Ethyl methyl ester

1,4-dihydro-4- [3 - [[[[3- (4-phenyl-1-piperidinyl) propyl] amino] carbonyl] amino] phenyl] -2,6-dimethyl-3,5-pyridinedicarboxylic acid;

Ethyl methyl ester

1,4-dihydro-4- [3 - [[[[3 - [(4-phenylmethyl) -1-piperidinyl] propyl] amino] carbonyl] amino] phenyl] -2,6-dimethyl-3,5-pyridinedicarboxylic acids;

Ethyl methyl ester

1,4-dihydro-4- [3 - [[[3 - [[4-hydroxy-4- (2-methoxyphenyl) piperidin-1-yl] propyl] amino] carbonyl] amino] phenyl] -2,6 dimethyl-3,5-pyridinedicarboxylic acid;

Ethyl methyl ester

1,4-dihydro-4- [3 - [[[[3- [4-hydroxy-4- (3-methoxyphenyl) piperidin-1-yl] propyl] amino] carbonyl] amino] phenyl] -2,6 dimethyl-3,5-pyridinedicarboxylic acid;

Dimethyl ester

1,4-dihydro-2,6-dimethyl-4- [3 - [[[[3- [4- [3- (2-propoxy) phenyl] -1-piperidinyl] propyl] amino] carbonyl] amino] phenyl] -3,5-pyridinedicarboxylic acid;

1,4-dihydro-4- [3 - [[[[[2- [4 - [(3-methoxyphenyl) -1-] piperidinyl] ethyl] amino] carbonyl] amino] phenyl] dimethyl ester] -2,6- dimethyl-3,5-pyridinedicarboxylic acid, hydrochloride;

Dimethyl ester

1,4-dihydro-4- [3 - [[[[4- [4- (3-methoxyphenyl) -1-piperidinyl] butyl] amino] carbonyl] amino] phenyl] -2,6-dimethyl-3,5 -pyridinedicarboxylic acid, hydrochloride;

Dimethyl ester

1,4-dihydro-4- [3 - [[[[3- [4- (3-methoxyphenyl) -1-piperidinyl] propyl] methyl-amino] carbonyl] amino] phenyl] -2,6-dimethyl-3 5-pyridinedicarboxylic acid hydrochloride;

Dimethyl ester

4-dihydro-4- [3 - [[[[3- [1,2,3,6-tetrahydro-4- (3-methoxyphenyl) pyridin-1-yl] propyl] amino] carbonyl] amino] phenyl] - 2,6-dimethyl-3,5-pyridinedicarboxylic acid;

Dimethyl ester

1,4-dihydro-4- [3 - [[[[3- (1,2,3,6-tetrahydro-4-phenylpyridin-1-] yl) propyl] amino] carbonyl] amino] phenyl] -2, 6-dimethyl-3,5-pyridinedicarboxylic acid;

Dimethyl ester

1,4-dihydro-4- [3 - [[[[3- [1,2,3,6-tetrahydro-4- (3-hydroxyphenyl) pyridine] propyl] amino] carbonyl] amino] phenyl] -2, 6-dimethyl-3,5-pyridinedicarboxylic acid;

Dimethyl ester

1,4-dihydro-4- [3 - [[[[3-1,2,3,6-tetrahydro-4- (1-naphthalenyl) -1-] pyridinyl] propyl] amino] carbonyl] amino] phenyl] -2,6-dimethyl-3,5-pyridinedicarboxylic acid;

Dimethyl ester

1,4-dihydro-4- [3 - [[3- (4-phenylpiperidin-1-yl) -1-oxo-1-propyl] amino] phenyl] -2,6-dimethyl-3,5-pyridinedicarboxylic acid ;

Dimethyl ester

1,4-dihydro-4- [3 - [[4- (4-phenylpiperidin-1-yl) -1-oxo-1-butyl] amino] phenyl] -2,6-dimethyl-3,5-pyridinedicarboxylic acid ;

Dimethyl ester

1,4-dihydro-4- [3 - [[5- (4-phenylpiperidin-1-yl) -1-oxo-1-pentyl] amino] phenyl] -2,6-dimethyl-3,5-pyridinedicarboxylic acid ;

Dimethyl ester

1,4-dihydro-4- [3 - [[6- (4-phenylpiperidin-1-yl) -1-oxo-1-hexyl] amino]] phenyl] -2,6-dimethyl-3,5-pyridinedicarboxylic acids;

Dimethyl ester

1,4-dihydro-4- [3 - [[5- (4-hydroxy-4-phenylpiperidin-1-yl) -1-oxo-1-] pentyl] amino] phenyl] -2,6-dimethyl-3 5-pyridinedicarboxylic acid;

Dimethyl ester

1,4-dihydro-4- [3 - [[5- (4-cyano-4-phenylpiperidin-1-yl) -1-oxo-1-pentyl]] amino] phenyl] -2,6-dimethyl-3 5-pyridinedicarboxylic acid;

Dimethyl ester

1,4-dihydro-4- [3 - [[[4 - [[4- (3-methoxyphenyl) -1-piperidinyl] butyl] carbonyl] amino] phenyl] -2,6-dimethyl-3,5-pyridinedicarboxylic acids;

Dimethyl ester

1,4-dihydro-4- [3 - [[[[3- [4- (3-methoxyphenyl) -1-piperidinyl] propyl] oxy] carbonyl] amino] phenyl] -2,6-dimethyl-3,5 -pyridinedicarboxylic acid, hydrochloride;

Dimethyl ester

1,4-dihydro-4- [3 - [[[[3- [4- (3-methoxyphenyl) piperidin-1-yl] propyl] amino] carbonyl] amino] phenyl] -2,6-dimethyl-3 5-pyridinedicarboxylic acid;

Dimethyl ester

1,4-dihydro-4- [3 - [[[[3- [4- (2-methoxyphenyl) piperidin-1-yl] propyl] amino] carbonyl] amino] phenyl] -2,6-dimethyl-3, 5-pyridinedicarboxylic acid;

Dimethyl ester

1,4-dihydro-4- [3 - [[[[3- [4- (3-hydroxyphenyl) piperidin-1-yl] propyl] amino] carbonyl] amino] phenyl] -2,6-dimethyl-3, 5-pyridinedicarboxylic acid;

Dimethyl ester

1,4-dihydro-4- [3 - [[[[3 - [[4-naphthalenylpiperidin-1-] yl] propyl] amino] carbonyl] amino] phenyl] -2,6-dimethyl-3,5-pyridinedicarboxylic acids

Dimethyl ester

4- [3 - [[[[3- (4-cyclohexyl-1-piperidinyl) propyl] amino] carbonyl] amino] phenyl] -1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid;

Dimethyl ester

1,4-dihydro-4- [3 - [[[[3- [1,2,3,6-tetrahydro-4- (3-methoxyphenyl) pyridin-1-yl] propyl] amino] carbonyl] amino] phenyl ] -2,6-dimethyl-3,5-pyridinedicarboxylic acid;

Dimethyl ester

1,4-dihydro-4- [3 - [[[3- [1,2,3,6-tetrahydro-4- (1-naphthalenyl) pyridin-1-yl] propyl] amino] carbonyl] amino] phenyl- 2,6-dimethyl-3,5-pyridinedicarboxylic acid.

Reference: see US Patent No. 5668151

As described in this context, it has been found that when administered to humans, PYY reduces appetite. When infused to humans at physiological levels corresponding to levels after a meal, PYY _3-36 significantly reduces appetite and reduces food absorption by one third within 12 hours and one third even within 24 hours. Both the effect itself and the duration of the effect are unexpected and unpredictable, as they continue for many hours after the hormone is removed from the blood circulation. The effects that are generated by using physiological levels of the peptide are strong indications that the action of PYY in vivo is to regulate eating behavior.

As described in this context, the peripheral administration of PYY _3-36 induces an increase in c-fos immunoreactivity in the arcuate nucleus of the hypothalamus and a decrease in the mRNA level of the hypothalamic neuropeptide Y (NPY) in rats. In addition, electrophysiological studies have shown that PYY _3-36 inhibits nerve endings containing NPY and thus activates POMC neurons, which are known to have inhibitory synaptic NPY inputs.

Regardless of theory, these results demonstrate that the intestinal hormone PYY _3-36 can act through the Y2 neuropeptide Y receptor. This assumption supports the observation that when PYY _{3-36 is} administered to mice lacking the Y2 neuropeptide Y receptor (mice that have knocked out gene Y2R), no inhibition of food absorption is noted. The introduction of PYY _{3-36 to the} offspring of wild-type data in mice lacking Y2R gives the full effect of suppressing food absorption.

Thus, a new pathway has been described connecting the gut and the brain, which suppresses nutrition after feeding. Regardless of theory, the natural pathway includes the release of PYY from the gut and its conversion into PYY _3-36 , which acts as an agonist of the neuropeptide Y receptor Y2 (NPY receptor Y2) in the brain. The Y2 NPY receptor acts as an inhibitory presynaptic receptor that reduces the output of neuropeptide Y, which is the most powerful nutrition stimulant, and also affects anorexigenic melanocortin systems. As a result, the activity of the Y2 NPY receptor suppresses appetite and reduces food absorption. The action of PYY _3-36 can be carried out in the arcuate nucleus of the hypothalamus, but other areas can also be involved.

The results show that the intestinal hormone PYY _3-36 , which circulates in the blood, suppresses appetite in physiological concentrations and that the inhibitory effect is observed even several hours after the hormone is removed from the blood. This effect is shown in all studied species, i.e. in mice, rats and humans. The intestinal hormone circulating in the blood appears to act through the hypothalamus cycle. A decrease in the level of mRNA necessary for the synthesis of appetizing regulatory hormones of the brain, in particular, hypothalamic NPY mRNA, may be a possible mechanism of long-term action of PYY _3-36 .

The description of the invention is illustrated by the following non-limiting Examples.

EXAMPLES

Example 1

Materials and methods

Preparation of POMC-EGFP Mice: The EGFP cassette contains its own Kozak translation initiation consensus site along with SV40 polyadenylation signals, which are located downstream of the EGFP coding sequences and direct the corresponding processing of the 3 ′ end of the EGFP mRNA. The EGFP cassette is introduced by standard techniques into the 5 ′ untranslated region of exon 2 of the mouse Roma mouse genomic clone, which contains 13 ′, 5 ′ and 3 ′ flanking sequences. and 2 kb, respectively (see Young et al., J. Neurosci. 18: 6631-40, (1998)). The transgene is introduced by microinjection into the pronuclei of C57BL / 6J mouse embryos at the single-cell stage (Jackson Laboratories), as described in Young et al. (see J. Neurosci. 18: 6631-40, (1998)). Get the founder of the line and cross it with wild type C57BL / 6J in order to obtain homizygous N1 mice. In addition, N2 and subsequent generations of mice homozygous for this transgene are also obtained. Mice are fertile and have normal growth and development.

Immunofluorescence and GFP colocalization: Mice under anesthesia are transcardially injected with 4% paraformaldehyde and free-floating sections of the brain are prepared in a vibratome. Sections were processed to obtain immunofluorescence and to determine the colocalization of GFP fluorescence using standard techniques. The following primary antiserum and its dilutions are used: rabbit against β-endorphin 1: 2500 vol./about .; rabbit vs. NPY, 1: 25,000 v / v (Alanex Corp.); rabbit versus ASTN, 1: 2000 v / v and murine against TH, 1: 1000 v / v. (Incstar). After washing, sections were incubated with 10 mg / ml biotinylated horse IgG against mouse, rabbit (Vector Laboratories), followed by treatment with Cy-3-conjugated streptavidin, 1: 500 vol./about. (Jackson Immunoresearch Laboratories). Microphotographs are taken with Zeiss Axioscop using the FITC and RITC filter kits (Chroma Technology Corp.).

Electrophysiology (Example 2): Coronal sections 200 μm thick are made from ARC male four week old POMC-EGFP mice. Sections are maintained in a medium containing (in mM) NaCl 126; KCl 2.5; MgCl ₂ 1,2; CaCl ₂ .2H ₂ O 2.4; NaH ₂ PO ₄ .H ₂ O 1, 2; NaHCO ₃ 21.4; glucose 11.1 (Krebs), at 35 ° C and a saturation of 95% O ₂ and 5% CO ₂ for 1 hour (h) before recording the results. Registration is carried out in Krebs medium at 35 ° C. Sections were visualized using Axioskop FS2 (Zeiss) using standard infrared optics and epifluorescence through a set of FITC filters (see Figure 1C). Whole cell data is recorded from fluorescent neurons using the Axopatch 1D amplifier (Axon Instruments) and Clampex7 (Axon Instruments). The resting membrane potentials are determined using an event detection protocol in the PowerLab system (AD Instruments, Mountain View, CA) to average the extended membrane potential records obtained on the registration instrument. Medicinal substances are introduced into the container at the indicated points in time. The resting resting membrane potential remains stable for an hour in cells treated only with Krebs. IV curves for Met-Enk currents are determined using a stepwise protocol; (the supported potential is -60 mV, pulsating sequentially (40 ms) from -120 to -50 mV, the cells return to -60 mV for 2 s between voltage surges). The protocol is repeated after adding Met Enk. The mains current is the difference between the two IV curves. This protocol is repeated in Krebs medium containing 6.5 mM K ⁺ . IV curves for determining the postsynaptic leptin current are determined in a similar manner using a slow linear voltage change (5 mV / s from -100 to -20 mV) before and within 10 minutes after the administration of leptin (100 nM). GABAergic IPSCs are recorded using an internal solution for CsCl electrodes containing (in mM): CsCl 140; Hepes 10; MgCl ₂ 5; Bapta 1; (Mg) -ATP 5; (Na) -GTP 0.3. In untreated sections, both mini IPSCs and high amplitude IPSCs (obviously multisynaptic) are observed. TTX (1 μM) removes large IPSCs. The data were obtained before and after the addition of the drug substance for the time points indicated in the Figures, with a supporting potential of -50 mV and oscillations of 2 s for every 4 s. Minipost synaptic currents are analyzed using Axograph 4 (Axon Instruments). IPSCs and excitatory postsynaptic currents (EPSCS) are separated by extinction constants; additional administration of picrotoxin (100 μM) blocks all IPSCs. POMC neurons receive a low EPSC signal, and none of the actions described in this context modulate the frequency.

Immunostaining for light and electron microscopy: A double immunocytochemical reaction for NPY and POMC using diaminobenzidine chromogens (DAB) of different colors is carried out on the fixed hypothalamus of mice in accordance with published protocols (see Horvath et al., 51,391-9, (1992) )). Electron microscopy for immunostaining for β-endorphin before material conclusion uses the ABC Elite kit (Vector Laboratories) and a DAB reaction followed by material conclusion. Moreover, after the conclusion of GABA and NPY labeled rabbit anti-GABA in a ratio of 1: 1000 vol./about. and gold (10 nm) conjugated goat anti-rabbit IgG or sheep anti-NPY and gold conjugated (25 nm) goat anti-sheep IgG. Finally, the sections were contrast stained with saturated uranyl acetate (10 minutes) and lead citrate (20-30 s) and examined using a Philips CM-10 electron microscope.

Animals: Male Wistar rats (weighing 200-250 g), aged 7-8 weeks (Charles River Laboratories, United Kingdom) are kept under controlled temperature (21-23 ° C) and lighting conditions (light from 07:00 to 19: 00) with free access to water and feed (diet RM1; SDS Ltd., Witham, United Kingdom) except as agreed. Cannula and injection into the arcuate and paraventricular nuclei is carried out as described previously (see Glaum et al., Mol. Pharmacol., 50: 230-5, (1996); Lee et al., J. Physiol. (Lond) 515 : 439-52, (1999); Shiraishi et al., Nutrition, 15: 576-9, (1999)). The correct position of the cannula within the nucleus is confirmed histologically at the end of each study period (see Glaum et al., Mol. Pharmacol., 50: 230-5, (1996); Lee et al., J. Physiol. (Lond), 515 : 439-52, (1999); Shiraishi et al., Nutrition, 15: 576-9, (1999)). All animal procedures are approved by the British Home Office Animals (Scientific Procedures Act, 1986. All injected animal starvation studies are performed during the early light phase (08: 00-09: 00) All injections during nutrition studies during the dark phase are carried out immediately before the lights are turned off.

Male Pomc-EGFP mice were examined at 5-6 weeks of age and prepared as described above. Mice, Y2r-null, are obtained using Cre-Pox P mediated recombination, which results in a germline deletion of the entire coding region of the Y2 receptor. All Y2r-null mice are supported on a mixed background of C57 / B16-129SvJ. Male mice aged 8-12 weeks and weighing 2-30 g are kept at a controlled temperature (21-23 ° C) and lighting (light on from 06:00 to 18:00) with free access to water and food (Gordon's Specialty Stock feeds), unless otherwise specified. All studies are carried out during the early light phase (07: 00-08: 00).

Intraperitoneal injections: Rats adapt to intraperitoneal injections by intraperitoneal injection of 0.5 ml of saline two days before the study. In all studies, animals were given an intraperitoneal injection of either PYY _3-36 or physiological saline in a volume of 500 μl (for rats) or 100 μg (for mice).

Electrophysiology: Patch clamp recording instruments (potential fixation) in whole cells are recorded from POMC neurons in coronal sections of the hypothalamus 180 μm thick Pomc-EGFP mice as previously described (see Cowley et al., Nature, 411: 480-484 , (2001)). Recordings of recording instruments freely attached to the cells are made using extracellular buffer in an electrode solution and maintaining an insulating resistance between 3 and 5 mOhm during recording. The number of pulses is determined using minianalysis protocols (MiniAnaLysis, Jaejin Software, NJ). Carrier controls used in this system are pre-tested in terms of the electrophysiological effect of neuropeptides (see Cowley et al., Nature, 411: 480-484, (2001)). Data is analyzed by ANOVA, posthoc Neuman-Keuls comparison, and Wilcoxon relative rank test.

Hypothalamic explants: Male Wistar rats are sacrificed by decapitation and immediately the whole brain removed is fixed with the ventral surface up and placed in a vibrating microtome (Biorad, Microfield Scientific Ltd., Dartmouth, UK). A 1.7 mm thick slice is obtained from the base of the brain so that it contains PVN and ARC and is immediately transferred to 1 ml of artificial CSF (cerebrospinal fluid) (aCSF) (see Kim et al., J. C1in. Invest ., 105: 1005-11, (2000)), which is balanced with 95% O ₂ and 5% CO ₂ and maintained at 37 ° C. After an initial 2-hour equilibration period with aCSF replaced every 60 minutes, hypothalamic samples are incubated for 600 minutes in 600 μl of aCSF (baseline) before treatment with Y2A (50 nM) in 600 μl of aCSF. Finally, tissue viability is checked by treatment with 56 mM KCl for 45 minutes; isotonicity is maintained by replacing K ⁺ with Na ⁺ . At the end of each period, aCSF is removed and frozen at -20 ° C until radioimmunoassay for NPY and aMSH is performed.

C-fos expression: C-fos expression was measured in mature Wistar rats and Pomc-EGFP mice 2 hours after intraperitoneal administration of saline or PYY _3-36 (5 μg / 100 g) using standard immunohistochemical techniques (see Hoffman and et al., Front. Neuroendocrinol., 14: 173-213, (1993)). Data are obtained from groups of 3 rats and 5 mice each. For Pomc-EGFP mice, 5 anatomically close sections of the arcuate nucleus were counted in each animal (see the monograph by Franklin et al., Mouse Brain in Stereotaxic Coordinates (The Mouse Brain in Stereotaxic Coordinates), Academic Press, San Diego, (1997)) and imaging using a Leica TSC confocal microscope (see Grove et al., Neuroscience, 100: 731-40, (2000)).

RNase Protection Assay (RPA): Total RNA is extracted from the hypothalamus (Trizol, Gibco). RPAs are carried out (RPAIII kit, Ambion) using 5 μg RNA and probes specific for NPY, aMSH and β-actin (internal standard). For each neuropeptide, the ratio of the optical density of the neuropeptide mRNA band to the optical density of β-actin is calculated. Neuropeptide mRNA expression levels are expressed relative to the control as physiological saline (mean ± s.e.m., n = 4 / group). Statistical analysis uses ANOVA with post hoc Bonferroni analysis.

Plasma assays: Commercially available radioimmunonalysis (RIA) (Unco Research, USA) is used to measure human leptin. The levels of all other plasma hormones are measured using the developed RIA (see Tarling et al., Intensive Care Med., 23: 256-260, (1997)). Glucose concentrations were measured using a YSI 2300STAT analyzer (Yellow Springs Instruments Inc., Ohio, USA). Plasma paracetamol levels are measured using an enzyme colorimetric assay (Olympus AU600 analyzer).

Human studies: PYY _3-36 purchased from Bachem (California, USA). The test using Limulus amoebocyte lysate for pyrogens is negative, and the peptide is sterile when administered with respect to cultures. Ethical approval is obtained from the Local Research Ethics Committee (Project registration 2001/6094) and the research is conducted in accordance with the principles of the Helsinki Declaration. Subjects give written consent based on the information received.

Each subject undergoes a study twice with an interval of at least 1 week between each of the studies. Volunteer experiment participants fill out a nutrition diary three days before each infusion and the next 24 hours. All subjects are starving and drinking only water from 8:00 p.m. evening, prior to each of the studies. Subjects arrive at 08:30 on each day of the study, they are given a cannula and allowed to rest for 30 minutes before the start of the study protocol. Blood samples were taken every 30 minutes in heparinized tubes containing 5000 units of a kallikrein inhibitor (0.2 ml) aprotinin (Bayer), and centrifuged. Plasma is separated and then stored at -70 ° C until analysis. Subjects are either injected with saline or 0.8 pmol.kg ^-1 .min ^-1 PYY _3-36 for 90 minutes (total infusion is approximately 72 pmol) in a double-blind randomized mixed format.

Two hours after the end of the infusion, subjects are offered a free choice of excess snacks (see Edwards et al., Am. J. Physiol. Endocrinol. Metab., 281: E155-E166, (2001)) so that all can be satisfied appetites. Food and water are weighed before and after meals and calorie intake is calculated. Appetite scores are made using 100 mm visual analogue accounting systems (VAS) with texts expressing the most positive and negative scores attached to each end (see Raben et al., Br. J. Nutr., 73: 517-30 , (1995) .VAS is used to assess hunger, satiety, satiety, expected food intake and nausea. Calorie intake after saline and PYY _{3-36 are} compared using Student's paired criterion. Food response curves are compared using ANOVA using repeated paired measurements taking into account factors such as time and treatment option.

Measurement of energy expenditures: To determine the effect of PYY on energy expenditures, the OXYMAX system in rodents is used after injection of PYY in the treatment group. This system is also used in rodents after injection of saline (control group). The equipment measures the consumption of O ₂ and the formation of CO ₂ , while the efficiency with which the body forms CO ₂ from O ₂ gives a reliable coefficient of the efficiency of using calories or metabolism. A similar system is used on people - voluntary participants in the experiment.

Example 2

The nervous network in the arcuate core

A line of transgenic mice expressing a green fluorescence protein (Clontech EGFP) is obtained under transcriptional control of the genomic sequences of Pomc mice, which include a region located between -13 kb. and -2 kb necessary for precise expression in neurons (see Young et al., J. Neurosci., 18: 6631-40, (1998)) (see Figure 1a). Bright green fluorescence is observed in two regions of the central nervous system, where POMC is formed - in the ARC and single pathway nucleus. Under ultraviolet light (450-480 nm), POMC neuron excitation clearly differs from neighboring non-fluorescent neurons (see Figure 1b) visualized using infrared optics. Double immunofluorescence shows> 99% cell colocalization of the EGFP and POMC peptides in ARC (see Figure 1c). There is a close overlap of the ends stained with tyrosine hydroxylase (TH) and NPY on POMC neurons expressing EGFP, but there is no evidence of colocalization of TH or NPY immunoreactivity with EGFP. The total number of fluorescent cells on the coronal slices of the hypothalamus is 3148 + 62 (mean ± SEM: N = 3) POMC-EGFP neurons distributed as a whole by ARC (see Franklin et al., Stereotactic mouse brain (The Mouse Brain in Stereotaxic Coordinates), Academic Press, San Diego, (1997)) (see Figure 1d). Mouse POMC neurons are located in the ARC both medially and ventrally, in contrast to the predominantly lateral position in rat ARC.

POMC-EGFP neurons in sections of the hypothalamus have a resting resting membrane potential of -40 to -45 mV and exhibit frequent spontaneous action potentials. The non-selective opioid agonist met-enkephalin (Met-Enk, concentration 30 μM; Sigma) causes fast (35–40 s) reversible hyperpolarization (10–20 mV) of the POMC cell membrane potential (N = 10) and prevents the spontaneous generation of the action potential (see . Figure 2a). In a normal (2.5 mM K ⁺ ) Krebs buffer, the reversible potential of the incoming rectifying opioid current is approximately -90 mV, while in 6.5 mM K ⁺ Krebs buffer the reversible potential shifts to approximately -60 mV (n = 3, see Figure 2b). The STAP mu-opioid receptor antagonist (MOP-R) (at a concentration of 1 μM; Phoenix Pharmaceuticals) completely suppresses the current induced by Met-Enk in POMC cells (n = 3, see Figure 2c). These characteristics show that the opioid current is due to the activation of MOP-R and increased ion conductivity through internally regulated potassium channels associated with the G-protein (GIRK) (Kelly et al., Neuroendocrinology, 52: 268-75, (1990)).

Reactions to opioids in EGFP-labeled POMC neurons similar to reactions in POMC cells of guinea pigs (see Kelly et al., Neuroendocrinology, 52: 268-75, (1990)) or mice (see Slugg et al., Neuroendocrinology , 72: 208-17, (2000)), identified by immunohistochemical reactions after registration, suggest that the expression of the EGFP transgene does not violate either the expression of receptors or binding to secondary carrier systems in POMC neurons.

Next, the direct effect of leptin on identified POMC cells in section preparations is examined. Leptin (at a concentration of 0.1-100 nM) causes depolarization in 72 of 77 POMC cells at 3-30 mV (see Figure 3a; average depolarization ± SEM when exposed to leptin at a concentration of 100 nM = 9.7 ± 1.2 mV, n = 45) for 2-10 minutes depending on the concentration (see Figure 3b). Two components are involved in depolarization and none of them is completely restored within 40 minutes. First, depolarization is due to the small incoming current, which is reversible at approximately −20 mV (see Figure 3c), which suggests participation in a non-specific cation channel (see Powis et al., Am. J. Physiol., 274: R1468-72, (1998)). Secondly, the effect of leptin reduces the GABAergic signal on POMC cells. GABAergic inhibitory postsynaptic currents (IPSCs) are observed in POMC cells and leptin (at a concentration of 100 nM) reduces their frequency by 25% (see Figure 3d) in 5 out of 15 cells. This suggests that it acts presynaptically, decreasing the GABA output (leptin has no effect on IPSCs in 10 out of 15 POMC neurons). The effect on the IPSC frequency is similar to the effect on the membrane potential. Thus, it not only directly causes the depolarization of POMC neurons, but also acts on GABAergic nerve endings, decreasing the GABA output on POMC neurons, which allows them to accept a more depolarized resting potential. The existing depolarization of POMC cells with leptin is specific, since leptin does not affect 5 of the 13 examined non-fluorescent cells studied (see Figure 3e), while it causes hyperpolarization of 5 (see Figure 3f) and depolarization of 3 other non-POMC neurons in ARC. The electrophysiological effects of leptin described in this context correspond to the biological activity of leptin; leptin quickly causes the release of o-MSH from rat hypothalamus (see Kim et al., J. Clin. Invest., 105: 1005-11, (2000)), primarily by activation of POMC neurons.

Previous reports of hyperpolarization of neurons by leptin (see articles Glaum et al., Mol. Pharmacol., 50: 230-5, (1996); Spanswick et al., Nature, 390: 521-5, (1997)) and demonstrated colocalization GABA and NPY (see Horvath et al., Brain Res., 756: 283-6, (1997)) in subpopulations of ARC neurons suggest that leptin causes hyperpolarization of NPY / GABA cells that directly innervate POMC neurons and thus Thus, it reduces the GABAergic effect on POMC cells. Both leptin and Y2 NPY receptors are expressed on neurons containing NPY in ARC (see Hakansson et al., J. Neurosci. 18: 559-72, (1998); Broberger et al., Neuroendocrinology 66: 393-408, (1997)). Moreover, activation of Y2 receptors suppresses NPY output from neurons containing NPY (see King et al., J. Neurochem., 73: 641-6, (1999)) and probably also minimizes GABA output from terminations NPY / GABA. This provides an alternative pharmacological approach, independent of leptin, for testing the hypothetical innervation of POMC neurons by GABAergic neurons containing NPY. Indeed, NPY (at a concentration of 100 nM; Bachem) reduces the frequency of GABAergic IPSCs by 55% for 3 minutes in all 12 POMC cells studied (see Figure 4a). Both NPY and leptin also inhibit IPSCs in the presence of tetrodotoxin (TTX) (in 6 of 6 and 3 of 5 cells, respectively), showing that some inhibition of IPSCs is due to direct effects on presynaptic nerve endings. POMC neurons express the Y1 NPY receptor (see Broberger et al., Neuroendocrinology 66: 393-408, (1997)) and NPY also cause hyperpolarization of all tested POMC neurons by an average of 9 ± 6 mV (n = 3).

Another pharmacological test to confirm the nature of GABAergic innervation on POMC neurons from NPY / GABA terminations is to test the effect of the recently characterized and highly selective MC3-R D-Trp ⁸ -γMSH agonist (see Grieco et al., J. Med. Chem. 43 : 4998-5002, (2000)) to the local exit of GABA. D-Trp ⁸ -γMSH (at a concentration of 7 nM) increases the frequency of GABAergic IPSCs (280 ± 90%) recorded for 3 of 4 POMC neurons (see Figure 4b). It does not act on one cell. The positive effect of MC3-R activation together with the negative effects of NPY and leptin demonstrates the dynamic range of the NPY / GABA synapse on POMC neurons and indicates the important role of this synapse in modulating signal conduction in ARC. D-Trp ⁸ -γMSH (at a concentration of 7 nM) also causes hyperpolarization (-5.5 ± 2.4 mV) of 9 of the 15 POMC neurons studied and reduces the frequency of action potentials (see Figure 4c). In the remaining cells, there is no significant response to D-Trp ⁸ -γMSH. These effects cannot be entirely due to the increased GABAA release of POMC cells and could be associated with an additional postsynaptic effect of D-Trp ⁸ -γMSH on POMC neurons, of which about half also express MC3-R (see Bagnol et al., J Neurosci. (In press), 19: RC26, (1999)). Thus, MC3-R acts in a similar way to MOP-R in an autoreceptor manner on POMC neurons, minimizing the activity of POMC neurons in response to an increased level of POMC peptides.

To further determine that IPSCs in POMC neurons are caused by local innervation by NPY / GABA cells, immunohistochemical studies with many labels are performed using light and electron microscopy. Although the dependent innervation of NPY has been described (see Csiffary et al., Brain Res., 506: 215-22, (1990)) and GABA (see Horvath et al., Neuroscience, 51: 391-9, (1992) ) on POMC cells, the colocalization of NPY and GABA in synapses forming nerve endings is not shown. Similar to data in rats (see Csiffary et al., Brain Res., 506: 215-22, (1990)), dense innervation of POMC cells with NPY axon endings was found in mice (see Figure 4d). Electron microscopy data confirm the coexpression of NPY and GABA at the ends of the axons and show that these synapses forming “buds” (complexes) are at the periphery of all 15 POMC ARC neurons analyzed (representative example, see Figure 4e).

A detailed regulation model of this cycle shows paired mechanisms of leptin action in ARC, interactions between NPY / GABA and POMC neurons and autoregulatory feedback with opioid and melanocortin peptides, as well as NPY (see Figure 4f). In this model, leptin directly causes the depolarization of POMC neurons and, at the same time, hyperpolarization of the soma of neurons and reduces the output of their NPY / GABA terminations. This reduced GABA output removes inhibition of POMC neurons and results in activation of POMC neurons and an increased frequency of action potentials.

Example 3

Introduction PYY Suppresses Food Absorption

The systems of orexigenic NPY and anorectic α-melanocortin-stimulating hormone (α-MSH) of the arcuate nucleus of the hypothalamus are involved in the central regulation of appetite (see Schwartz et al., Nature, 404: 661-671, (2000)). However, the potential mechanisms for transmitting the food uptake signal directly to these hypothalamic closed food chains remain unclear. PYY _3-36 is a hormone secreted from the gut that comes out after ingestion in proportion to the number of calories consumed (see Pedersen-Bjergaard et al., Scand. J. C1in. Lab. Invest., 56: 497-503, (1996 )). Investigate the effects of peripheral administration of PYY3-36 on nutrition.

Intraperitoneal injection (IP) of PYY _3-36 to rats with a free diet before the onset of the dark phase significantly reduces subsequent absorption of food (see Figure 5a). A similar inhibition of nutrition was observed after IP injection in rats subjected to fasting for 24 hours (see Figure 5b). In a temporary aspect, plasma PYY _3-36 levels achieved after IP injection of PYY _3-36 show a peak level 15 minutes after injection, which lies in the range of normal levels after a meal (peak PYY _3-36 levels 15 minutes after IP injection 0.3 μg / 100 g = 99.3 ± 10.4 pmol / L relative to the peak level after ingestion = 112.1 ± 7.8 pmol / L n = 8-10 / group). This suggests that physiological concentrations of PYY _3-36 inhibit nutrition. PYY _3-36 does not affect gastric emptying (the percentage of absorbed food stored in the stomach after 3 hours is for PYY _3-36 = 36 ± 1.9%, for saline = 37.4 ± 1.0% n = 12) (see article Barrachina et al., Am. J. Physiol., 272: R1007-11, (1997)). PYY _3-36 with intraperitoneal administration twice a day for 7 days reduces the cumulative absorption of food (7-day cumulative absorption of food is for PYY3-36 = 187.6 ± 2.7 g relative to the data for physiological saline = 206.8 ± 2.3, n = 8 / group, P <0.0001) and reduces body weight gain (see Figure 5d) (PYY _3-36 = 48.2 ± 1.3 g relative to saline = 58.7 ± 1 , 9, n = 8 / group, P <0.002).

Example 4

The introduction of PYY affects the expression of c-fos

To investigate whether the hypothalamic pathway is involved in this suppression of food intake, c-fos expression is examined in the arcuate nucleus, an important center for nutrition control (see Schwartz et al., Nature, 404: 661-671, (2000); Cowley et al. ., Nature, 411: 480-484, (2001)) after a single intraperitoneal injection of PYY3-36. In the lateral arc of rats, a twofold increase in the number of c-fos positive cells was noted (PYY3-36 = 168 ± 2, saline = 82.7 ± 5, n = 3, P <0.0001). Similarly, in transgenic Pomc-EGFP mice (see Cowley et al., Nature, 411: 480-484, (2001)), intraperitoneal administration of PYY_3-36 at the result leads to a 1.8-fold increase in the number of arc cells positive for c-fos (see Figure 6b) compared to control animals injected with saline (see Figure 6a) (PYY_3-36= 250 ± 40, physiological saline = 137 ± 15, n = 5, P <0.05). IP introduction PYY_3-36 causes a 2.6-fold increase in the ratio of POMC neurons that express c-fos (PYY_3-36= 20.4 ± 2.9%, saline = 8 ± 1,%, n = 5, P <0.006) (see Figures 6c and d).

Observation data suggest that PYY _3-36 can act through an arcuate core. As a result, PYY _3-36 and its effects on the NPY and POMC pathways in the hypothalamus are studied. Due to delayed food suppression and the effects of weight gain after peripheral administration of PYY _3-36, hypothalamic messenger RNA (mRNA) of both Pomc and NPY is measured using RNase protection assays. A significant decrease in NPY mRNA in response to PYY _{3-36 is} observed 6 hours after IP injection compared with animals injected with saline (saline = 17.3 ± 2.0, PYY3-36 = 8.8 ± 1, 0, relative units of optical density, P <0.02). A slight increase in POMC mRNA levels is noted.

Example 5

Y2 receptors

PYY _3-36 shows a 70% amino acid sequence identity with NPY and acts through NPY receptors (see Soderberg et al., J. Neurochem., 75: 908-18, (2000)). Y2R is thought to be an inhibitory presynaptic receptor and is expressed at a high level on neurons containing NPY of the arcuate nucleus (see Broberger et al., Neuroendocrinology 66: 393-408, (1997)), although it is not expressed on neighboring POMC neurons. PYY _3-36 is a high affinity Y2 receptor agonist (Grandt et al., Regul. Pept, 51: 151-159, (1994)). It is believed that peripheral PYY _3-36 inhibits food uptake through Y2R in the arcuate nucleus, an area known to be directly accessible to the action of hormones circulating in the blood (see Kaira et al., Endocr. Rev. 20: 68-100 , (1999)).

To examine this hypothesis, PYY _{3-36 is} injected directly into the arcuate core (see Kim et al., Diabetes, 49: 177-82, (2000)). In rats subjected to starvation for 24 hours, food intake is significantly reduced at such low doses as 100 fmol (see Figure 7a), which results in a suppression similar to that observed after IP administration. In order to determine whether these effects are mediated through Y2R, a selective Y2R agonist is used (see Potter et al., Eur. J. Pharmacol., 267: 253-262, (1994)), N-acetyl (Leu 28 , Leu 31) NPY24-36) [Y2A]. Its affinity is confirmed in receptor binding studies (see Small et al., Proc. Natl. Acad. Sci. USA, 94: 11686-91, (1997)) on cell lines expressing NPY Y1, Y2, and Y5 receptors (Y2 has an IC ₅₀ = 1.3 + 0.2 nM, IC ₅₀ Y1> 5000 nM, IC ₅₀ Y5> 5000 nM). The introduction of Y2A into the arcuate nucleus of rats that were previously starved for 24 hours in a dose-dependent manner (100 fmol - 1 nmol) inhibits food absorption (feed absorption 2 hours after injection is 0.1 nmol Y2A = 6.2 ± 0, 5 g, for physiological saline = 8.2 ± 0.6 g, n = 8 / group, P <0.05).

To confirm the anatomical specificity of this effect, Y2A (100 fmol - 1 nmol) is injected with paraventricular nucleus (PVN) (see Kim et al., J. C1in. Invest., 105: 1005-11, (2000)) rats, subjected to starvation for 24 hours, and did not detect changes in food intake (2 hours after injection: saline = 8.3 ± 0.4 g, 0.1 nmol Y2A = 8.0 ± 0.6 g, n = 8 / group). To further determine the role of Y2R in the suppression of nutrition caused by the peripheral administration of PYY _3-36 , the effect of PYY _3-36 in mice lacking Y2r and control offspring is examined. PYY _3-36 inhibits daytime nutrition in a dose-dependent manner in fasted wild-type mice, but does not inhibit food absorption in fasted mice lacking Y2R (see Figures 7b and 7c). Food absorption, measured as a response to starvation, demonstrates that male mice lacking Y2r eat significantly more after 2, 4, and 24 hours compared to their control offspring (24-hour cumulative food intake; mice lacking Y2R = 7.1 ± 0.48 g relative to the wild type = 5.3 ± 0.7 g, n = 8 / group, P <0.05).

The electrophysiological reaction of the POMC hypothalamic neurons to the administration of both PYY _3-36 and Y2A is examined. These neurons are identified using mice with targeted expression of green fluorescence protein in POMC neurons (see Cowley et al., Nature, 411: 480-484, (2001)). PYY _3-36 removes the inhibition of POMC neurons, which results in significant depolarization of 19 of the 22 POMC neurons studied (see Figure 8a, inset) (depolarization 10.3 + 2.1 mV, n = 22, P <0.0003 ) A similar depolarization is observed when using Y2A (depolarization of 8.7 ± 1.8 mV, n = 9, P <0.002). Depolarization caused by PYY _3-36 stimulates a significant increase in the frequency of action potentials in POMC neurons (see Figure 8a) (93% increase relative to control, P <0.05, n = 22). In the whole-cell format, the effect of PYY _{3-36 is} sometimes removed by washing, but only after a long delay (30 minutes). On these neurons, similar effects of a similar leptin washing are observed.

To eliminate the effects of cell depletion or damage to the integrity, the effect of PYY _3-36 in a configuration with the addition of free cells (or extracellular configuration) is examined. PYY _3-36 causes a reversible 5-fold increase in the frequency of action potentials in the POMC neuron registration records when using free cell attachment (see Figure 8b). This increase in the number of excitation pulses occurs with the same delay with which PYY _3-36 reduces the frequency of inhibitory postsynaptic currents (IPSCs) on all 13 POMC neurons studied (see Figure 8c) (51.9 ± 9.2% reduction, n = 13, P <0.0001), which indicates a reduced frequency of GABA release to POMC neurons. Interestingly, the number of impulses of the POMC neurons returns to the baseline, despite the continuous inhibition of IPSCs. A similar effect with respect to the IPSC frequency is observed when using Y2A (a decrease of 44.4 + 9.3%, n = 8, P <0.004), which suggests the mediation of this effect through Y2R. PYY3-36 (at a concentration of 25 nM) causes hyperpolarization (5.2 ± 1.16 mV, P <0.004, n = 5) of unidentified but presumably NPY-containing non-POMC neurons in the arcuate nucleus. Tonic GABAergic inhibition of POMC neurons by NPY-containing neurons was noted (see Cowley et al., Nature, 411: 480-484, (2001)), and these results suggest that the action of PYY _3-36 is to inhibit neurons containing NPY neurons, and thus reducing the GABAergic signal and, therefore, removing inhibition of POMC neurons. The effect of Y2A on peptide secretion using hypothalamic explants is also investigated (see Kim et al., J. Ctin. Invest., 105: 1005-11, (2000)). Y2A significantly reduces the yield of NPY while increasing the yield of a-MSH from hypothalamic explants (see Figures 8d and 4e). Taken together, the observational data suggest that PYY _3-36 modulates both NPY and melanocortin systems in an arcuate core.

Example 6

Human Research

Due to the importance of the melanocortin system to humans (see Barsh et al., Nature, 404: 644-651, (2000)) and the profound effects of PYY _3-36 on both nutrition and the change in body weight observed in rodents, they are exploring the effects of PYY _3-36 on human appetite and food absorption. Twelve starved obese volunteers (six men and six women, average age 26.7 ± 0.7 years, BMI = 24.6 ± 0.94 kg m ^-2 ) inject PYY _3-36 (0.8 pmol.kg ^-1 .min ^-1 ) or physiological saline for 90 minutes in a double-blind study in a mixed way with a placebo control.

Plasma concentrations of PYY _3-36 increase from an average base concentration of 8.3 ± 1.0 pM to 43.5 ± 3 pM during the PYY _3-36 infusion and mimic post-meal levels (see Pedersen-Bjergaard et al. , Scand. J C1in. Lab. Invest., 56: 497-503, (1996), Adrian et al., Gastroenterology, 89: 1070-1077, (1985)). Concentrations of PYY _3-36 achieved after infusion are returned to baseline within 30 minutes. PYY _3-36 infusion results in a significant reduction in hunger scores (see Raben et al., Br.J. Nutr., 73: 517-30, (1995)) (see Figure 9c), but do not cause drowsiness or weaknesses. Calorie consumption with a free choice of snacks (see article Tarling et al., Intensive Care Med., 23: 256-260, (1997)) two hours after the end of the infusion decreases by more than one third relative to saline (36 ± 7 , 4%, p <0.0001) (see Figure 9a). There is no effect on fluid absorption and differences in the sensation of satiety and nausea described by voluntary participants in the experiment. The administration of PYY _{3-36 has} no effect on gastric emptying as determined by the paracetamol absorption method (see articles by Edwards et al., Am. J. Physiol. Endocrinol. Metab., 281: E155-E166, (2001); Tarling et al., Intensive Care Med., 23: 256-260, (1997)) or on plasma glucose, plasma levels of GLP-1 leptin or insulin. Analysis of food diaries shows a significant suppression of food absorption during the 12-hour period after the infusion of PYY3-36 (saline = 2205 ± 243 kcal, PYY3 = 1474 ± 207 kcal). However, the absorption of food between 12 and 24 hours is virtually identical in the two groups. Overall, a 33% decrease in cumulative total calorie intake over a 24-hour period after PYY _3-36 infusion was observed (see Figure 9b). These facts demonstrate that infusion of PYY _3-36 in concentrations corresponding to levels after a meal causes a significant suppression of both appetite and food absorption in humans.

An additional study involved two groups of healthy subjects (n = 12 / group, 6 men and 6 women), one - subjects with an increased body mass index (BMI) (average index = 32.73 ± 0.93 kg / m ² ) and the other group is subjects with low BMI (average index = 20.49 ± 2.05 kg / m ² ). Groups undergo a study twice with an interval of at least 1 week between each study. All subjects starve and drink only water from 8 p.m. evening, prior to each of the studies. Subjects arrive at 08:30 on each day of the study, they are given a cannula and allowed to rest for 30 minutes before the start of the study protocol. Subjects are either injected with saline or 0.8 pmol.kg ^-1 .min ^-1 PYY _3-36 for 90 minutes in a double-blind randomized mixed format. Two hours after the end of the infusion, subjects are offered a free choice of snacks in excess so that all appetites can be satisfied. Food and water are weighed before and after meals and calorie intake is calculated. The number of calories consumed after administration of saline and PYY _{3-36 is} compared using the paired student criterion (p <0.001). The number of calories consumed after administration of PYY _3-36 significantly differs from the number of calories consumed after administration of physiological saline in both groups — the overweight group and the group of lean subjects (subjects without excess body weight). For the overweight group, a decrease of 28.8 ± 4.3% is shown, and for the group without overweight, a decrease of 31.1 ± 4.4%. However, a decrease in the overweight group does not have significant differences with a decrease in the group without overweight. These facts demonstrate that infusion of PYY _3-36 at a concentration corresponding to levels after a meal causes a significant suppression of both appetite and food absorption in both subjects - overweight and not overweight.

Regardless of theory, cells in an arcuate nucleus could detect peripheral saturation signals and transmit these signals to other areas of the brain (see Butler et al., Nature Neuroscience, 4: 605-611, (2001)). This assumption is supported by the observation that leptin modifies the activity of neurons in the POMC arcuate nucleus and containing NPY (see Cowley et al., Nature, 411: 480-484, (2001)). The results presented in this context demonstrate on the basis of a complex of electrophysiological studies and studies of hypothalamic explants that the intestinal hormone PYY _3-36 can directly affect the hypothalamic cycles, which as a result leads to coordinate changes in the action of POMC and NPY. The presented results show that neurons containing NPY in the ARC are not protected by the blood-brain barrier and, as a result, are accessible to molecules circulating in the circulatory system. Moreover, PYY _3-36 introduced directly into this area of the brain reduces food absorption.

The results presented in this context demonstrate that PYY _3-36 levels after ingestion inhibit food intake in more than one mammal species (e.g., rodents and humans) for up to 12 hours, thus demonstrating their role in regulating absorption food. This role can be defined as a long-acting effect, such as lasting for several hours (for example, at least two, three, four, eight or twelve hours, or from about two to about fifteen hours). These compounds differ from previously characterized “short-term” saturation signals from the gut, such as cholecystokinins (see Schwartz et al., Nature, 404: 661-671, (2000); Moran, Nutrition, 16: 858-865, (2000 )), the effects of which are relatively short-lived (for example, from about 1 to 4 hours).

The inability of PYY _{3-36 to} inhibit food uptake in Y2R-null mice proves that PYY _3-36 reduces food uptake by acting through a Y2R-dependent mechanism. The results presented in this context suggest the presence of a new intestinal-hypothalamic pathway in nutrition regulation, including the effect of PYY _3-36 at the post-food level on the Y2R of the arcuate nucleus. Thus, PYY and its analogues, such as PYY _3-36 , are therapeutic agents for treating obesity.

There is no doubt that the exact details of the described methods and compositions may be changed or modified within the spirit of the described invention. All these modifications and variations that are included in the scope and essence of the following claims are claimed.

Claims (50)

1. A method of modifying eating behavior, characterized in that the peripheral administration of PYY to the subject is carried out in an amount effective to achieve physiological levels of PYY _3-36 in blood, plasma or serum determined after a meal, or peripheral administration of the PYY agonist to the subject is carried out in an amount effective to mimic the physiological levels of PYY _3-36 in blood, plasma or serum, determined after a meal with a modification of eating behavior, by reducing calorie intake, food intake or sn a decrease in appetite or an increase in energy consumption in a subject. 2. The method according to claim 1, characterized in that the subject is overweight. 3. The method according to claim 1, characterized in that the subject is obese. 4. The method according to claim 1, characterized in that the subject suffers from diabetes. 5. The method according to claim 1, characterized in that the peripheral administration of PYY or a PYY agonist includes oral, subcutaneous, intravenous, intramuscular, intranasal, transdermal, intracisternal, intravaginal, intraperitoneal, local, transmucosal, buccal, rectal or sublingual pulmonary inhalation. 6. The method according to claim 5, characterized in that the dose of PYY or its agonist is from about 45 to about 135 pmol / kg of subject body weight. 7. The method according to claim 6, characterized in that the dose of PYY or its agonist is approximately 72 pmol / kg of body weight of the subject. 8. The method according to claim 1, characterized in that PYY or its agonist is administered at least 30 minutes before a meal. 9. The method according to claim 1, characterized in that the peripheral administration of PYY or its agonist is carried out repeatedly, each dose being administered in an amount of from about 0.5 to about 135 pmol / kg of subject body weight at least about 30 minutes before administration food. 10. The method according to claim 1, characterized in that the subject is also administered a therapeutically effective amount of an additional appetite suppressing agent, which is ampepramone (diethylpropion), phentermine, mazindol, phenylpropanolamine, fenfluramine, dexfenfluramine or fluoxetine. 11. The method according to claim 1, characterized in that PYY or its agonist is administered to the subject in an amount effective to reduce his calorie intake for at least 2 hours. 12. The method according to claim 11, characterized in that PYY or its agonist is administered to the subject in an amount effective to reduce his calorie intake for about 2 to 24 hours. 13. The method according to claim 1, characterized in that the subject is a human. 14. The method according to claim 1, characterized in that the PYY agonist contains a molecule that specifically binds to the Y2 receptor. 15. The method according to 14, characterized in that the PYY agonist increases the expression of c-fos in the part of the arcuate nucleus in contact with the PYY agonist. 16. The method according to claim 1, characterized in that the PYY agonist specifically binds to a neuron containing a neuropeptide Y, and inhibits the activity of a neuron containing a neuropeptide Y. 17. The method according to clause 16, wherein the PYY agonist reduces the pulse rate of the action potential of the neuron containing the neuropeptide Y. 18. The method according to clause 16, wherein the neuron containing the neuropeptide Y is synaptically linked to the proopiomelanocortin neuron, wherein the binding of the PYY agonist to the neuron containing the neuropeptide Y leads to an increase in the activity of the proopiomelanocortin neuron. 19. The method according to p. 18, characterized in that the PYY agonist, binding to a neuron containing a neuropeptide Y, reduces the pulse rate of the action potential of a neuron containing a neuropeptide Y, while reducing the activity of a neuron containing a neuropeptide Y, leads to increased generation of potential the action of the proopiomelanocortin neuron. 20. The method according to claim 1, characterized in that they achieve a decrease in appetite in the subject. 21. The method according to claim 20, characterized in that achieve a reduction in food intake by the subject. 22. The method according to item 21, characterized in that they achieve a reduction in calorie intake by the subject. 23. The method according to claim 1, characterized in that they achieve the prevention or reduction of weight gain of the subject. 24. The method according to claim 1, characterized in that they achieve the induction or maintenance of weight loss of the subject. 25. The method according to claim 1, characterized in that PYY or its agonist is administered in an amount of from about 0.5 to about 135 pmol / kg of body weight of the subject. 26. The method according to claim 1, characterized in that they achieve the induction or enhancement of saturation and the sensation of saturation in the subject. 27. The method according to claim 1, characterized in that the suppression of hunger and hunger sensations in a subject are achieved. 28. The method according to claim 1, characterized in that the peripheral administration to the subject of PYY or its agonist is carried out repeatedly or in separate doses. 29. The method according to claim 1, characterized in that the peripheral administration to the subject of PYY or its agonist is carried out by peripheral injection in a pulse dose. 30. The method according to claim 1, characterized in that the peripheral administration of PYY or its agonist is carried out in a form that provides sustained, prolonged or controlled release of the drug, or using a pump or implantable device for drug administration. 31. The method according to claim 1, characterized in that the peripheral administration of PYY or an agonist thereof is carried out in a dose of from about 5 to about 50 nmol. 32. The method according to claim 1, characterized in that the dose of PYY or its agonist is from about 2 to about 20 nmol. 33. The method according to p, characterized in that the dose of PYY or its agonist is approximately 10 nmol. 34. The method according to claim 1, characterized in that the subject is administered a therapeutically effective amount of an additional agent that suppresses appetite. 35. The method according to claim 1, characterized in that the subject is additionally administered at least one of the agents that reduce the level of glucose in blood plasma, agents that change the content of lipids in blood plasma, or agents that reduce food intake. 36. The method according to claim 1, characterized in that the subject achieves maintaining the desired body mass or maintaining the desired body mass index. 37. The method according to claim 1, characterized in that the subject suffers from a disorder or is at risk for a disorder whose risk factor is obesity or overweight. 38. The method according to claim 1, characterized in that the subject suffers from a disorder caused, complicated or aggravated due to the relatively high availability of nutrients. 39. The method according to claim 1, characterized in that a PYY agonist is administered to a subject suffering from a disorder caused by complicating or aggravating due to the relatively high availability of nutrients. 40. The method according to claim 1, characterized in that the physiological levels of PYY _3-36 in blood, plasma or serum after a meal are from 40 to 60 pM. 41. The method according to p, characterized in that the physiological levels of PYY _3-36 in blood, plasma or serum after a meal are from 40 to 50 PM. 42. The method according to claim 1, characterized in that PYY is PYY _3-36 . 43. The method according to § 42, wherein PYY _3-36 is administered in an amount of from about 0.5 to about 135 pmol / kg of subject body weight. 44. The method according to § 42, wherein PYY _3-36 is administered in an amount of from about 45 to about 135 pmol / kg of body weight of the subject. 45. The method according to § 42, wherein PYY _3-36 is administered in an amount of approximately 72 pmol / kg of subject body weight. 46. The method according to § 42, wherein PYY _3-36 is administered in an amount of from about 1 to about 100 nmol. 47. The method according to claim 1, characterized in that the subject is administered PYY. 48. The method according to claim 1, characterized in that the subject is administered a PYY agonist. 49. The use of PYY or an agonist thereof as a means of modifying eating behavior in order to reduce weight in a subject by reducing calorie intake, food intake, or reducing appetite, or increasing energy consumption in a subject. 50. The use of PYY or an agonist thereof as an active ingredient in the manufacture of a medicament for modifying eating behavior to reduce weight in a subject by reducing calorie intake, food consumption, or reducing appetite, or increasing energy consumption in a subject.

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