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WO2012027825A1 - Méthode de traitement de troubles neuropsychiatriques associés à la dopamine - Google Patents

Méthode de traitement de troubles neuropsychiatriques associés à la dopamine Download PDF

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Publication number
WO2012027825A1
WO2012027825A1 PCT/CA2011/000968 CA2011000968W WO2012027825A1 WO 2012027825 A1 WO2012027825 A1 WO 2012027825A1 CA 2011000968 W CA2011000968 W CA 2011000968W WO 2012027825 A1 WO2012027825 A1 WO 2012027825A1
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pyrrolidineacetamide
analogue
paopa
dopamine
disorder
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Inventor
Rodney Johnson
Ram K. Mishra
Bailey Dyck
Dipannita Basu
Michael Beyaert
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McMaster University
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McMaster University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to the use of pyrrolidineacetamide analogues in a method of treating dopamine-related neuropsychiatric disorders.
  • Dopamine-related neuropsychiatric disorders is meant to refer to neurological disorders or mental illnesses resulting from abnormal dopamine neurotransmission
  • Dopamine is a catecholamine neurotransmitter that activates the five types of dopamine receptors— Di, D 2 , D 3 , D 4 , and D 5 and their variants. There are a number of dopaminergic innervated pathways within the brain, including the mesocortical, mesolimbic, nigrostriatal, and tuberoinfundibular. As a neurotransmitter, dopamine functions as a mediator of glutamatergic and GABAergic neurotransmission, and plays important roles in mood, memory, learning, attention, reward, and addiction. Dopamine is also a neurohormone released by the hypothalamus. Its main function as a hormone is to inhibit the release of prolactin from the anterior lobe of the pituitary. Dopamine is found in a wide variety of animals, including both vertebrates and invertebrates.
  • Dopamine-related neuropsychiatric diseases and disorders such as schizophrenia, bipolar disorder and autism spectrum disorder (ASD) are complex diseases that frequently affect an individual's performance in many physiological and cognitive functions.
  • pharmaceutical drugs used to treat these mental and neurological disorders are dopamine D2 receptor antagonists which result in severe adverse side effects.
  • Pharmaceutical agents currently used to treat these disorders are typically agents that help normalize the dopamine dysregulation characterizing these disorders. These include a range of dopamine receptor agonists and/or antagonists. However, complete stimulation or inhibition of these receptors can result in severe side effects such as movement and metabolic disorders.
  • Schizophrenia is a serious mental disorder affecting 1 % of the population.
  • SZ can manifest in various ways but it is often characterized by the appearance of positive symptoms (hallucinations, delusions, disorganized behaviour) and negative symptoms (alogia, affective blunting, avolition, anhedonia/associality) and cognitive dysfunction (impairment in attention, episodic and working memory, speed of information processing, and executive functioning).
  • Its etiology involves multiple factors such as genetic predisposition, psychosocial factors, alterations in neurotransmitter systems, viral infections, and changes in neuroanatomical structures. Abnormalities in multiple neurotransmitter systems have been implicated in the etiology of schizophrenina, although dopaminergic dysregulation is the most widely accepted hypothesis.
  • ASD Autism Spectrum Disorders
  • Behavioral and cognitive abnormalities which affect children at a young age. Symptoms often include impairments in social behaviour and cognitive function.
  • symptoms can be treated with a wide range of pharmacological agents that affect the dopaminergic system, such as antidepressants and antipsychotic drugs.
  • Bipolar disorder is a mood disorder that is characterized by a cycling between manic and depressive episodes. Features of manic episodes include elevated mood, hyperactivity and grandiose delusions. Antipsychotic drugs that affect dopaminergic neurotransmission, such as olanzapine and risperidone, are commonly prescribed for the treatment of BD.
  • AD Alzheimer's disease
  • patients exhibit severe, irreversible cognitive decline, including memory loss, impaired judgement, and decreased attention-span.
  • the dopamine system has been implicated as patients often display psychotic symptoms at later stages, and current treatments for this disorder influence dopamine release.
  • Lewy body disease is a type of dementia, which is characterized by the formation of protein aggregates in neuronal cells, resulting in cell loss, including the loss of dopaminergic neurons. Patients often exhibit psychotic-like hallucinations, and cognitive symptoms. There is currently no cure, although this disease can be treated with typical antipsychotic drugs.
  • DADs Drug Addictive Disorders
  • BADs Behaviour Addictive Disorders
  • Addiction to a substance or behaviour is caused by exaggerated dopamine release in the nucleus accumbens in response to the stimulus.
  • Addictive agents and activities include smoking, drug abuse (including but not limited to cocaine, amphetamine, phencyclidine, alcohol, cannabis, methylenedioxymethamphetamine (MDMA)), gambling, food consumption, shopping, sex, and other impulse control disturbances. More treatment options are needed to treat these disorders and facilitate the withdrawal from the addictive agent or behavior. Psychological factors such as impaired judgment and impulsivity are at the core of these disorders.
  • Dopamine D2 receptor blocking agents are used as a first measure in schizophrenia therapy; however, both typical D2 receptor blocking agents, e.g. haloperidol, as well as atypical blocking agents, e.g. clozapine, olanzapine, and risperidone, cause serious adverse effects such as extra-pyramidal side effects (movement disorders), weight gain, metabolic adverse effects, and development of type 2 diabetes.
  • typical D2 receptor blocking agents e.g. haloperidol
  • atypical blocking agents e.g. clozapine, olanzapine, and risperidone
  • pyrrolidineacetamide analogues are useful in a method of treating a dopamine-related neuropsychiatric disorder in a mammal.
  • a method of treating a dopamine-related neuropsychiatric disorder in a mammal comprising administering to the mammal a therapeutically effective amount of a pyrrolidineacetamide analogue.
  • an article of manufacture comprising packaging material and a composition, wherein the composition comprises a pyrrolidineacetamide analogue and a pharmaceutically acceptable carrier, and the packaging material indicates that the composition is effective to treat a dopamine-related neuropsychiatric disorder.
  • FIGURE 2A/B graphically illustrate prevention and reversal of deficit in social interaction (negative symptom of schizophrenia) in an amphetamine-induced model of schizophrenia;
  • FIGURE 3 graphically illustrates prevention of hyperlocomotor activity (positive symptom of schizophrenia) by PAOPA;
  • FIGURE 4 A-E graphically illustrate prevention and reversal of deficit in social interaction (negative symptom of schizophrenia) in NMDA receptor blockade (MK801 ) model of schizophrenia;
  • FIGURE 5 graphically illustrates increased agonist (dopamine) induced- internalization of dopamine D2 receptor by PAOPA (a mechanism by which PAOPA prevents and reverses the schizophrenia-like behavioural abnormalities);
  • FIGURE 6 graphically illustrates increased agonist (quinpirole)-induced dopamine D2 receptor internalization by PAOPA
  • FIGURE 7 illustrates decreased abnormal involuntary movements (AIMS) with administration of PAOPA.
  • a method of treating a dopamine-related neuropsychiatric disorders in a mammal comprising administering to the mammal a therapeutically effective amount of a pyrrolidineacetamide analogue.
  • dopamine-related neuropsychiatry disorder is meant to encompass neurological or mental disorders, e.g. a psychological or behavioural pattern generally associated with subjective distress or disability, associated with dysfunction of dopaminergic neurotransmission. Examples of dopamine-related neuropsychiatric disorders include, but are not limited to, schizophrenia, autism spectrum disorders (ASD), bipolar disorder, Alzheimer's disease, Lewy body disease, and drug and behavioural addictions.
  • pyrrolidineacetamide analogue refers to compounds having the following general formula (1):
  • Rl , R2, R3, R4, R5, R6, R7 and R8 may be the same or different and may be H; OH; halogen; a -C1-C6 saturated or unsaturated alkyl group optionally substituted with one or more substituents selected from hydroxyl and halogen; Ci-C 6 alkanol; and Ci-C 6 alkoxy.
  • An example of such an analogue includes, but is not limited to, 3(R)-[(2(S)- pyrrolidinylcarbonyl)amino]-2-oxo-l -pyrrolidineacetamide (PAOPA).
  • Pyrrolidineacetamide analogues in accordance with the invention may be synthesized using well-established techniques.
  • the present method encompasses the treatment of dopamine-related neuropsychiatric disorders in a mammal.
  • the terms “treat”, “treating” and “treatment” are used broadly herein to denote methods that favourably alter the targeted disorder, including those that moderate or reverse the progression of, reduce the severity of, prevent, or cure the disorder.
  • mammal is used herein to encompass both human and non-human mammals.
  • therapeutically effective dosages of a pyrrolidineacetamide analogue are administered to a mammal to treat a dopamine-related neuropsychiatric disorder.
  • therapeutically effective refers to a dosage that is effective to treat a psychological disorder without causing unacceptable adverse side effects.
  • administered refers to any appropriate means of providing a pyrrolidineacetamide analogue to a mammal, and will depend on the dosage form being used as will be appreciated by one of skill in the art.
  • Therapeutically effective dosages according to the method may be in the range of 0.1-500 mg.
  • the preferable dose is between 1-20 mg.
  • the effective therapeutic dosage of a given pyrrolidineacetamide analogue will vary depending on many factors, including but not limited to, the type of disorder to be treated, the nature and severity of the disorder, the mammal to be treated, the symptoms of the mammal being treated, the compound used for the treatment, and the route of administration.
  • Pyrrolidineacetamide analogues may be administered by any number of routes including but not limited to oral, subcutaneous, intravenous, intraperitoneal, intranasal, enteral, topical, sublingual, intramuscular, intra-arterial, intramedullary, intrathecal, inhalation, ocular, transdermal, vaginal or rectal means.
  • routes including but not limited to oral, subcutaneous, intravenous, intraperitoneal, intranasal, enteral, topical, sublingual, intramuscular, intra-arterial, intramedullary, intrathecal, inhalation, ocular, transdermal, vaginal or rectal means.
  • These analogues may be administered either alone or in a composition combined with a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable means suitable for safe administration to mammals..
  • the selection of carrier depends on the intended mode of administration.
  • the compounds are formulated for administration by infusion or by injection either subcutaneously or intravenously, and are accordingly utilized as aqueous solutions in sterile and pyrogen-free form and optionally buffered or made isotonic.
  • the compounds may be administered in distilled water or, more desirably, in saline, phosphate-buffered saline or 5% dextrose solution.
  • compositions for oral administration via tablet, capsule, lozenge, solution or suspension in an aqueous or nonaqueous liquid, an oil-in-water or water-in-oil liquid emulsion, an elixir or syrup are prepared using excipients including: sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and derivatives thereof, including sodium carboxymethylcellulose, ethylcellulose and cellulose acetates; powdered tragancanth; malt; gelatin; talc; stearic acids; magnesium stearate; calcium sulfate; vegetable oils, such as peanut oils, cotton seed oil, sesame oil, olive oil and corn oil; polyols such as propylene glycol, glycerine, sorbital, mannitol and polyethylene glycol; agar; alginic acids; water; isotonic saline; and phosphate buffer solutions.
  • excipients including: sugars,
  • the composition may be formulated for application topically as a cream, lotion or ointment.
  • the composition may include an appropriate base such as a triglyceride base.
  • Such creams, lotions and ointments may also contain a surface active agent and other cosmetic additives such as skin softeners and the like, as well as fragrance.
  • Aerosol formulations for example for nasal delivery, may also be prepared in which suitable propellant carriers are used.
  • compositions for mucosal administration are also encompassed, including but not limited to, oral, nasal, rectal or vaginal administration.
  • Such compositions generally include one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax, a salicylate or other suitable carriers.
  • suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax, a salicylate or other suitable carriers.
  • Other carriers may also be added to the composition regardless of how it is to be administered which, for example, may aid to extend the shelf-life thereof.
  • a pyrrolidineacetamide analogue compound may be administered by any of a number of routes including but not limited to oral, subcutaneous, intravenous, intraperitoneal, intranasal, enteral, topical, sublingual, intramuscular, intra-arterial, intramedullary, intrathecal, inhalation, ocular, transdermal, vaginal or rectal means.
  • the present pyrrolidineacetamide compounds have been found to bind to the dopamine D2 receptor at an allosteric site rather than at the orthosteric site, or dopamine-binding site. This results in an increase in dopamine binding to the D2 receptor and maintains the receptor in an active state.
  • pyrrolidineacetamide analogues increase dopamine neurotransmission by increase dopamine D2 receptor stimulation, normalizing dopaminergic signalling.
  • pyrrolidineacetamide analogues can attenuate dopaminergic signalling via the following mechanisms.
  • the increase in the number of postsynaptic receptors in the active state induced by treatment with the present compounds causes internalization and down-regulation of the receptors, effectively decreasing the number of receptors available to transmit dopamine signals which compensates for the increase in dopamine. Furthermore, the increase in activation of pre-synaptic receptors induced by treatment limits dopamine synthesis and release, effectively decreasing the amount of dopaminergic neurotransmission. See data below for examples of the use pyrrolidineacetamide analogues to normalize dopamine-associated behavioural abnormalities in preclinical animal models.
  • the use of the present pyrrolidineacetamide analogues to treat neuropsychiatric disorders provide numerous advantages over current treatments.
  • the occurrence of adverse side effects such as those that commonly occur in current treatments, e.g. extrapyramidal symptoms (EPS), drug- induced tardive dyskinesia, Parkinsonian-like symptoms, prolactin secretion, weight gain, elevated blood glucose, elevated blood insulin, increased triglyceride levels, and an increased risk of developing diabetes mellitus and heart disease, is minimized.
  • EPS extrapyramidal symptoms
  • the effect of the present compounds is receptor-limited minimizing the toxicity thereof.
  • the present compounds have been determined to be soluble in body fluids such as blood and cerebral spinal fluid, and thus, are effectively absorbed, distributed throughout the body on administration and eliminated. Their solubility also results in low effective doses, and lower production costs.
  • an article of manufacture comprises packaging material and a composition.
  • the composition comprises a pyrrolidineacetamide analogue and a pharmaceutically acceptable carrier.
  • the packaging material includes an indication that the composition is effective to treat a dopamine-related psychiatric disorder.
  • Amphetamine was prepared as follows: 1 mg/mL for week one, 2 mg/mL for week two, 3 mg/mL for week three.
  • PAOPA was synthesized by Dr. Rodney Johnson at the University of Minnesota, as previously described by Yu et al. (Yu et al, 1988) and prepared as a 1 mg/mL solution each week.
  • escalating doses of D-amphetamine were prepared with 1 mg/mL PAOPA.
  • a 3 week drug withdrawal period followed the injections, during which the rats were not handled.
  • PPI of the acoustic startle response refers to the reduction of a startle-eliciting "pulse” stimulus when it is shortly preceded by a weak "prepulse” stimulus. PPI is an unlearned phenomenon and can be shown using almost identical techniques and parameters, with similar sensitivity to stimulus parameters in mice, rats and humans (Tenn et al, 2003).
  • Startle responses were assessed using the SR-Lab Startle Response System (San Diego Instruments, and prepulse intensities were adapted from Tenn et al. (Tenn et al, 2003;Tenn et al, 2005). Briefly, startle reflexes were measured in four identical startle chambers. Each lighted, ventilated, sound-attenuated chamber contained a stabilimeter consisting of a non-restrictive Plexiglas cylinder mounted on a Plexiglas platform. Cylinder movements were detected by a piezoelectric accelerometer mounted under the Plexiglas platform and were digitized and stored by the interfacing computer assembly.
  • PPI testing began by bringing the animals to the testing room 1 hour before testing began. After this transition time, each rat was placed in the startle apparatus for a 5 min acclimatization period, with a 64 dB white noise present in the background. After this period, each mouse was presented with a series of five startle pulse-alone (HOdB) trials. This series of stimuli was followed by 64 randomized trials consisting of no pulse (0 dB, background noise present), a startle pulse (1 10 dB, 40 ms) or one of three prepulse intensities (67, 70, and 73 dB, 20 ms) presented alone or 100 ms preceding the startle pulse. Lastly, another series of five startle pulse-alone trials was presented. Intertrial times ranged from 10 to 20s to average 15s.
  • Results displayed in Figure 3 show prevention of hyperlocomotor activity in an amphetamine-induced model, suggesting PAOPA's usefulness and therapeutic effect in the treatment of positive symptoms of schizophrenia.
  • rats were allocated to test partners on the basis of knockout, wild type or heterozygous genotype, with body weight differences between the two partners kept within lOg.
  • Social behaviour was tested for a 5 min period, with no acclimation time allotted.
  • the time spent in social interaction was recorded [in milliseconds (ms)], with interaction including sniffing, following, crawling under or over, grooming, and aggressive behaviour.
  • ms milliseconds
  • Results displayed in Figure 2A/B show prevention and reversal of social withdrawal in amphetamine induced pre-clinical model of schizophrenia, suggesting the usefulness of PAOPA in the treatment of negative symptoms of schizophrenia.
  • PAOPA causes an increase in the number of dopamine D2 receptors in the active state.
  • HEK293 human embryonic kidney cells were stably transfected with the DA D2 receptor, and the machinery required for internalization of the overexpressed receptor, including G-protein coupled receptor kinase-2 (GRK2), and arrestin-3.
  • GRK2 G-protein coupled receptor kinase-2
  • a tetracycline-regulated expression line of HEK293 (T-Rex-293) cells was grown in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine calf serum and 5mg/mL blasticidin. Cells were incubated at 37°C and 5% C0 2 and passaged weekly.
  • DMEM Dulbecco's modified Eagle's medium
  • Bovine GRK2 was subcloned into pCDNA4/TO (Zeocin-resistant), rat arrestin 3 was subcloned into pcDNA5/TO (hygromycin-resistant) and dopamine D2S receptor cDNA with a FLAG epitope at the amino terminus was fused into pCIN4 (G418-resistant) with an enhanced yellow fluorescence protein (eYFP) tag.
  • the constructs were serially transfected into the T-Rex-293 cells with Lipofectamine and resistant colonies were selected.
  • T-Rex-293 cells triply transfected with bovine GRK2, rat arrestin 3 and human D2S receptor were seeded onto poly (D)-lysine coated 24 well plates at a density of 2X10 5 cells per well, and induced overnight with tetracycline (1 ⁇ g/mL). The following day, cells were incubated in the presence of DMEM with 0.2 mM sodium metabisulfite (assay buffer). Wells received either assay buffer only (control) or assay buffer with drug treatment. Treatments included just agonist (30 ⁇ quinpirole or 10 ⁇ dopamine) or agonist and PAOPA (1 ⁇ or 10 ⁇ ), for 1 .5 hrs at 37° C.
  • [ 3 H]-sulpiride is a highly hydrophilic compound that only radioactively tags receptor remaining on the cell membrane, thus allowing for a quantification of percent receptor internalization.
  • Plates of drug-treated cells were quickly cooled on ice and washed three times with ice-cold Earle's Balanced Salt Solution (EBSS). The cells were then incubated with 6nM [ 3 H]-sulpiride at 4°C for 3.5 hrs. Non-specific binding was determined in the presence of ImM cold sulpiride. Cells were washed three times with ice-cold EBSS to removed unbound radioactivity. Cells were lifted by adding 1 % Triton-X 100 with 5mM EDTA, and placed into a scintillation vial with scintillation cocktail. Radioactivity counts were measured 24 hours later.
  • L-DOPA induced abnormal involuntary movements are the common adverse effects in PD patients treated with L-DOPA. Although the mechanisms of L-DOPA induced dyskinesias remains unknown, supersensitization of striatal dopamine receptors have been implicated. It was investigated whether or not PAOPA could block the development of AIMS.
  • AIMS were induced in 6-OHDA lesioned Sprague Dawley rats, by injecting (LP.) L-DOPA methyl ester 6 mg/kg combined with peripheral DOPA-decarboxylase inhibitor, benserazide (15 mg/kg, Sigma) for 3 weeks.
  • the AIMS were evaluated by previously published rating scales, (Lundblad et al., 2002).
  • AIMS were classified according to topographic distribution, forelimb, orolingual, axial, and locomotive behaviour. Forelimb and orolingual dyskinesias occur predominantly and hyperkinesias, and the axial dyskinesia occurs predominantly as dystonia. Locomotor dyskinesia was expressed as circling movements away from the lesioned side. Scores from 0 to 4 were used to indicate the severity of AIMS subtypes (0: absent, 1 : occasional, 2: present less than 50% of the time, 3: continuous but interrupted by strong sensory stimuli, and 4: continuous).
  • Table 1 Distribution of [ 3 H] PAOPA upon intraperitoneal administration ( 100,000 DPMs were injected).
  • PAOPA causes toxic effects in preclinical models.
  • PAOPA was injected into rats at various doses for 28 days.
  • the results set out below in Table 2 clearly show no toxic effects and animals did not display any abnormal movements or cognitive behaviours.

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Abstract

La présente invention concerne l'utilisation d'une quantité thérapeutiquement efficace d'un analogue de pyrrolidinacétamide, tel que POPOA, pour le traitement de troubles neuropsychiatriques associés à la dopamine tels que la schizophrénie, les troubles dans le spectre de l'autisme (ASD), les troubles bipolaires, la maladie d'Alzheimer, les maladies à corps de Lewy et les addictions médicamenteuses et comportementales.
PCT/CA2011/000968 2010-08-31 2011-08-26 Méthode de traitement de troubles neuropsychiatriques associés à la dopamine Ceased WO2012027825A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015027342A1 (fr) * 2013-08-30 2015-03-05 Mcmaster University Compositions de microgel pour le relargage de substances dans le cerveau
CN119504546A (zh) * 2023-11-28 2025-02-25 成都地奥制药集团有限公司 内酰胺环类化合物及其用途

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003030899A2 (fr) * 2001-10-08 2003-04-17 Ucb, S.A. Utilisation de derives de 2-oxo-1-pyrrolidine pour la preparation d'un medicament

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
WO2003030899A2 (fr) * 2001-10-08 2003-04-17 Ucb, S.A. Utilisation de derives de 2-oxo-1-pyrrolidine pour la preparation d'un medicament

Non-Patent Citations (2)

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Title
DYCK ET AL.: "PAOPA, a potent analogue of Pro-Leu-glycinamide and allosteric modulator of the dopamine D2 receptor, prevents NMDA receptor antagonist (MK-801)- induced deficits in social interaction in the rat: Implications for the treatment of negative symptoms in schizophrenia.", SCHIZOPHRENIA RESEARCH., vol. 125, 2011, pages 88 - 92 *
SHARMA, S ET AL.: "Pro-Leu-glycinamide and its peptidomimetic, PAOPA, attenuate haloperidol induced vacuous chewing movements in rat: A model of human tardive dyskinesia.", PEPTIDES., vol. 24, 2003, pages 313 - 319 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015027342A1 (fr) * 2013-08-30 2015-03-05 Mcmaster University Compositions de microgel pour le relargage de substances dans le cerveau
CN119504546A (zh) * 2023-11-28 2025-02-25 成都地奥制药集团有限公司 内酰胺环类化合物及其用途
WO2025113519A1 (fr) * 2023-11-28 2025-06-05 成都地奥制药集团有限公司 Composé cyclique lactame et son utilisation

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