CZ20001387A3 - Use of antagonist and its assembly - Google Patents

Abstract

A method of reducing food or addictive substance consumption in a mammal is disclosed. The method comprises administering to the mammal an effective amount of a D1/D5 antagonist or a D1/D5 partial agonist alone or in combination with other specified CNS agents.

Description

USE OF THE ANTAGONIST AND ITS COMPOSITION

Technical field

The present invention is directed to reducing the need for food and addictive substances in mammals. More specifically, the present invention relates to reducing the need in mammals for any dopamine mediated cravings involving food or addictive substances.

State of the art

Significant research has been focused on obesity, nicotine addiction, and substance abuse. The health care costs to society associated with obesity, tobacco use, and drug and alcohol abuse are very high. Many individuals who decide to lose weight, quit smoking, and/or abuse drugs or alcohol often relapse into their established patterns of behavior within a short time after completing a treatment program. This can often be due to subtle environmental cues that initiate the individual's craving for food or the substance they were abusing. Accordingly, it would be desirable to provide a substance that would suppress the craving for food and/or the substance of abuse in a susceptible mammal.

The use of antagonists in the treatment of drug addiction is known. U.S. Patent Nos. 4,973,586 and 5,302,716 disclose the use of Dt antagonists in the treatment of drug addiction. A dosage range of 0.02 mg/kg to 10 mg/kg has been suggested, with 2.0 mg/kg divided into 1 to 3 administrations per day being particularly suitable.

Speaiman et al., Neurochem.lnt. Vol. 20 Suppl., 99147S-152S (1992) found that cocaine is a potent reinforcer and is often used as a standard for enhancing the reinforcing effects of other drugs. When SCH 39166 was administered to monkeys, a threefold or greater increase in the dose of cocaine was usually necessary to reinstate characteristic self-administration behaviors.

Barrett-Larimore and Speaiman reported in Society for Neuroscience Abstracts 22(2): 925 (1996) that several formulations containing the D1 antagonist SCH 39166, _D2 antagonists, and _D3 / _D4 antagonists were all able to attenuate cocaine-seeking behavior in a model of impaired health.

Clifton, 1995 and Clifton, 1991 indicated that the D ₄ antagonists SCH 39166 and SCH 23390 had no effect on total food intake, food volume, or feed fraction up to 3 mg/kg.

• · • · · · • ·

Caine and Koob in The Journal of Pharmacology and Experimental Therapeutics Vol.270, No.1 pp. 209-218 (1994) describe tests of the D- antagonists SCH 39168 and SCH 23390 on cocaine and food self-reinforcement. The D- antagonists were found to have an effect on food self-reinforcement.

Chausmer and Ettenberg in Pharmacology Biochemistry and Behavior Vol.57, No.4 pp. 681-685 (1997) tested the effects of D1 and D2 antagonists on reinstatement of food reward properties. They found that the _D2 antagonist raclopride was sufficient to block the effects of reinstatement of food reinforcement, but the D antagonist, SCH 39166, was not. Nathan, Breskin and Batki in CNS Drugs 1998, Jul ₁₀ (1) pp. 43-59 summarize the results of the treatment of cocaine addiction with various drugs.

Lancet, Volume 347 pp.504-508 (February 14, 1996) reports that haloperidol has been tested for the desired reduction in substance abuse. However, this agent is reported to have significant adverse effects such as dysphoria, restlessness, or rigidity, which reduce the desire of individuals to take it.

It has been difficult to develop a substance that would prevent the need for food or addictive substances in mammals, especially humans, due to the lack of reliable animal models that closely match human behavior.

Substances that are administered to reduce cravings for food or addictive substances should not produce significant physiological effects such as mood stimulation or increased blood pressure or heart rate. This would lead to the substitution of one substance of abuse for another. Substances that suppress cravings for the substance of abuse should also not exacerbate the physiological symptoms of the substance of abuse if the individual has a relapse and takes the substance of abuse. Substances administered to reduce cravings for food or addictive substances should also not produce significant adverse effects such as dysphoria, restlessness, or rigidity.

Accordingly, it is desirable to provide a means and method of treatment that are active in reducing the need for the substance of abuse, that do not exacerbate the magnitude of the sympathetic response caused by the substance of abuse, and that have beneficial pharmacodynamic effects.

It is also desirable to provide a means and method of treatment that blocks the euphoric and dysphoric effects of the abused substance.

• · • · · · · * • · · · · * • · · · · · · · · · · · · · · *· ··

The essence of the invention

The present invention relates to the use of D1/D5 antagonists, D1/ _D5 partial agonists or mixtures thereof alone or in combination with other CNS agents for the preparation of a medicament for reducing cravings in a mammal, particularly cravings directed towards food and an addictive substance such as tobacco, alcohol, or drugs of abuse. In a preferred formulation, the D1/ _D5 antagonists, D1/D5 partial agonists are administered in the range of from 0.01 mpk to 500 mpk per day, preferably from 1 mpk to 150 mpk per day to a mammal susceptible to cravings for food or an addictive substance. Suitable Di/D ₆ antagonists are SCH 23390, SCH 39166, BTS-73-947, NNC-22-0010, JHS-271, JHS-198, JHS-136 and A 69024, with SCH 39166 being particularly suitable. A suitable Di/D ₆ partial agonist is SKF 38393.

Di/D ₆ antagonists or Di/D ₆ partial agonists may be used in combination with agents selected from the following CNS classes:

A. anti-obesity agents;

B. 5-hydroxytryptamine receptor agonists and antagonists;

C. antipsychotics/anxiolytics;

D. antidepressants;

E. dopaminergic agonists;

F. anticonvulsant/mood stimulants;

G. cocaine-like agonists;

H. cocaine catalytic antibodies; and

I. alcohol and opiate antagonist drugs.

An addictive substance is any substance that triggers the release of dopamine in susceptible mammals. Addictive substances include, but are not limited to, nicotine, alcohol, psychomotor stimulants such as amphetamines, opiates, benzodiazepines, and barbiturates. Craving is an intense and prolonged desire or craving for food or an addictive substance, often in response to environmental cues. The first dose of an addictive substance can trigger a relapse in mammals that have previously suppressed the seeking response to habit formation. A dopamine D1 site bioassay has been identified that would prevent the craving associated with withdrawal that is triggered by either a small dose of the addictive substance and/or associated cues. Pretreatment of the mammal helps • · · ·

Small doses of a D1/D5 antagonist or partial D1/D5 agonist suppress or block the need for food or an addictive substance.

While the examples presented below focus on DdD _s antagonists, it is contemplated that pure Dt antagonists, pure D§ antagonists, pure D1 partial agonists, and pure _Ds partial agonists and pure D1/ _Ds partial agonists will also demonstrate efficacy in reducing the need. Thus, the term "D1/Ds antagonist" as used herein includes agents that bind only to the _D5 receptor (pure _D5 antagonists) as well as agents that bind to both receptors. Similarly, the term "D1/D5 partial agonist" includes agents that bind only to the _D5 receptor (pure D1/ _D5 partial agonists) as well as agents that bind to both receptors and mimic dopamine under certain conditions. The term "mixtures thereof" is defined to include mixtures of two or more D1/D5 antagonists, two or more D2/D8 partial agonists, and one or more D1/ _D6 antagonists with one or more D1/ _D6 partial agonists. Suitable D1/ _D5 antagonists include;

SCH 39166, which has the chemical name (-)-trans-6,7,7a,8,9,13b-hexahydrQ-3-chloro-2-hydroxy-N-methyl-5H-benzo[d]-naphtho[2,1-bjazepine;

SCH 23390, which has the chemical name (d)-7-chloro-8-hydroxy-3-methyl-1-phenyl2,3,4,5-tetrahydro-1H-3-benzazepine maleate;

BTS-73-947, which has the chemical name 1-[1-(2-chlorophenyl)cyclopropyl-3-1,2,3,4-tetrahydro-7-hydroxy-6-methoxy-2-methyl-4-thioquinoline;

NNC-22-0010, which has the chemical name (+)-5-(5-bromo-2,3-dihydro-7-benzofuranyl)-8-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepin-?-ol;

JHS-271, which has the chemical name 8-chloro-3-[6-(dimethylamino)hexyl]-2,3-tetrahydro-5-phenyl-1H-3-benzazepin-7-ol;

JHS-198, which has the chemical name 8-chloro-3-[6-(dimethylamino)hexyl]2,3,4,5tetrahydro-5-phenyl-1H-3-benzazepin-7-ol with boranecarbonitrile (1:1);

JHS-136, which has the chemical name 8-chloro-3-[4-(dimethylamino)butyl]-2,3,4,5tetrahydro-5-phenyl-1H-3-benzazepin-7-ol; and • · · · · ·

A-69024, which has the chemical name 1-[(2-bromo-4,5-dimethoxyphenyl)methyl]-1,2,3,4tetrahydro-6-methoxy-2-methyl-7-isoquinolinol.

A suitable D1/D5 partial agonist is SKF 38393, whose chemical name is 2,3,4,5-tetrahydro-1-phenyl-1H-3-benzazepine-7,8-diol. The structures of these compounds are shown in Figures 14 and 15.

The compositions are suitably administered at a dose of from 0.01 mg/kg to 500 mg/kg per day, preferably from 1 mg/kg to 150 mg/kg per day. The efficacy of representative compositions in suppressing cravings can be seen from the following tests.

Overview of images in drawings

Figure 1 shows the effects of a D1/ _D5 antagonist and a D2/ _D5 antagonist on control locomotion as a function of dose.

Figure 2 shows the effects of a D1/ _D5 antagonist and a D2/D8 antagonist on locomotor control as a function of dose following cocaine administration.

Figures 4 and 5 show systolic and diastolic blood pressure in humans before and after cocaine administration as a function of time with different doses of a suitable D1/D5 antagonist and with placebo.

Figures 5 and 6 show heart rate and body temperature, each before and after administration of cocaine with different doses of a suitable D1/D2 antagonist _as a placebo. Figures 7 and 8 show subjective euphoria and anxiety, each before and after administration of cocaine with different doses of a suitable D2/D3 antagonist as a placebo.

Figure 9 depicts the subjective craving for cocaine as a function of time after administration of an appropriate D2 antagonist or placebo.

Figures 10 and 11 represent representations of subjective ratings of good and bad treatment effects, respectively, as a function of time and dose for individuals before and after cocaine administration.

Figures 12 and 13 present a representation of positive and negative behavioral responses as a function of time following administration of amphetamine and also following administration of the appropriate D antagonist D ₅ or placebo.

Figures 14 and 15 show the chemical structures of selected compounds.

• · · · · · • · · · • ·

Examples of embodiments of the invention

Example 1

Example 1 illustrates that a D₁/D₅ antagonist is effective in reducing the craving for the addictive drug, cocaine, while a _D₂ / _D₃ antagonist was more or less effective. Cocaine-induced increases in locomotor activity were blocked by a _D₁ / _D₅ antagonist, but not by _D₂ / _D₃ antagonists, unless relatively large doses were used. In this example, the selective D₁ antagonist, SCH 39166, and the selective _D₂ / _D₃ antagonist, raclopride, were studied on cocaine-induced locomotor stimulation in male CF-1 mice. Mice were given oral doses of SCH 39166, raclopride, or vehicle, followed 20 minutes later by a subcutaneous (s.c.) dose of cocaine or vehicle. Locomotor activity was measured 10 minutes later for a duration of 8 minutes and is shown in Figure 1. SCH 39166 or raclopride, when administered alone, produced a dose-dependent decrease in locomotor activity as shown in Figure 2. However, while SCH 39166 blocked the cocaine-induced increase in locomotor activity at all doses of cocaine tested, raclopride only adversely affected the cocaine-induced increase in locomotor activity at relatively high doses.

Example 2

This example demonstrates that the preferred DVD antagonist was effective and did not exhibit significant adverse effects when administered to subjects after cocaine injections. Subjects selected for these tests were individuals who had previously demonstrated cocaine addiction and were volunteers in the program. In a double-blind study, subjects were administered placebo, 10 mg SCH 39166, 25 mg SCH 39166, or 100 mg SCH 39166 two hours before an injection of 30 mg/kg cocaine. Systolic and diastolic blood pressure was measured in subjects from 2 hours before cocaine injection to 4 hours after cocaine administration. As can be seen in Figures 3 and 4 respectively, the DVD antagonist SCH 39166 did not adversely affect the increases in systolic and diastolic blood pressure caused by cocaine. Figure 5 shows that the baseline heart rate, in beats per minute, was not impaired after cocaine administration after SCH 39166, while Figure 6 shows that the increase in body temperature attributed to cocaine administration was not impaired.

•4 4444

4444 44 ··

4 4 4 · 4 4 ♦

4 4 4 4 ·

In the same study, cocaine craving was measured as a function of time after administration of placebo or various doses of SCH 39166. Cocaine craving was measured using the Visual Analytical Scale test. This method of testing is described in the British Journal of Medical Psychology, Vol.47, pp.211-217 (1984). In this test, subjects are asked to rate their subjective feelings of wanting to take cocaine on a scale of 0-100, where zero represents no craving at all and 100 represents the strongest feeling. As can be seen in Figure 7, the level of euphoria after cocaine administration was lower in patients who had been pretreated with SCH 39166, especially at a dose of 100 mg. Figure 8 shows that dysphoric effects, such as anxiety, were lower after cocaine administration in those patients who were pretreated with SCH 39166. As can be seen in Figure 9, cocaine craving was significantly lower compared to placebo in individuals who were administered SCH 39166. The greatest reduction in cocaine craving occurred in individuals who were administered 100 mg of SCH 39166.

Similarly, in a second crossover study in healthy volunteers administered 15 mg d-amphetamine after pretreatment with 100 mg SCH 39166 or placebo, attenuation of amphetamine euphoric (Figure 12) and dysphoric (Figure 13) effects was also observed with SCH 39166 compared to placebo.

Even if the compositions of the present invention were effective in reducing cravings for drugs or food, individuals would likely not use craving-reducing medications if they had tolerable side effects. Figure 10 shows that the "good effects of the drug," i.e., the individuals' favorable feelings toward the composition, were not significantly lower than placebo, even at a dose of 100 mg at 1.5 hours after administration, as measured by the Visual Analog Scale test. Figure 11 shows that the "bad effects of the drug" for all doses of SCH 39166 at the same time point, as assessed by the Visual Analog Scale test, were not significantly different from placebo. Therefore, the use of this composition should not be adversely affected by the negative perceptions of the individuals to whom the drug is administered, nor should it cause stimulation of subsequent administration.

Studies of food craving and reinstatement following food restriction in both rodent and primate models have shown that the D-/D ₅ antagonist SCH 39166 can block reinstatement associated with the effects of food and environmental food-related stimuli. While not wishing to be bound by any theory, Di/D ₅ antagonists and/or Di/D 5 partial agonists may prevent diet-induced reinstatement in the treatment of obesity by blocking the beneficial effects of dopamine in sites associated with food or drug craving.

·· ··♦·

Examples 3-5 provide further illustrations of the effect of a Dt/Dg antagonist in reducing food intake in a mammal.

Example 3

In this example, an adult male rat (strain: CD) was housed behind a pressure barrier on a fixed-time schedule of 30 (FR30). The rat was required to press the barrier 30 times to receive a single 45 mg food pellet. Each training session was 30 minutes long. The total response rate (total # of barrier presses/30 minutes), i.e. the rate at which the rats pressed the barrier, was measured and then analyzed in animals that were initially given saline (control animals) and then doses of the antagonists SCH 23390 or SCH 39168. Each group of six animals received a single dose of drug administered subcutaneously in a volume of 1 ml/kg 30 minutes before the start of the training session. The doses of SCH 23390 were 0.003 mg/kg, 0.005 mg/kg, 0.01 mg/kg, and 0.03 mg/kg (mpk), while the doses of SCH 39166 were 0.001 mg/kg, 0.003 mg/kg, 0.01 mg/kg, 0.03 mg/kg, 0.1 mg/kg, and 0.3 mg/kg (mpk). The 0.01 mg/kg (mpk) dose of both SCH 23390 and SCH 39166 significantly reduced the rate of pushing the bar relative to that of saline-treated control animals. Both drugs produced a dose-related decrease in the rate of responding until responses were eliminated at the highest dose.

Example 4 male mice from a genetically obese strain, i.e., ob/ob mice, at 16 weeks of age were individually housed in Nalgene metabolic cages under a reversed light cycle throughout the study. Mice were provided with food and water ad libitum. Mice were divided into 5 groups of 4-5 mice each based on baseline food intake and body weight. Mice were dosed intraperitoneally (ip) with 0.003 mg/kg, 0.03 mg/kg, 0.3 mg/kg, or 3.0 mg/kg SCH 39166 vehicle at the beginning of the night cycle and were provided with a known amount of standard rodent chow. Food consumption was measured after five hours and a further ip injection of vehicle was given. Food intake was measured again 24 hours after the initial injection. These injections and measurements continued for an additional 72 hours. 72 hour cumulative food intake was reduced by 17% at 3.0 mg/kg (p<0.02), ····

9 ·· ·· ··

Example 5

In this experiment, baseline food intake (in grams) was measured at time intervals of 2 hours, 4 hours, or 24 hours after intracerebral ventricular administration (i.c.v.) of neuropeptide “Y” (NPY), an agent that stimulates animals to consume food. A volume of 3 pg/5 μΙ NPY was administered to adult male Sprague-Dawley (SD) rats. Before the daily test, three groups of rats (five rats per group) were pretreated with SCH 39166 according to the following dosing schedule:

A dose of SCH 39166 was injected intraperitoneally (ip). Thirty minutes later, an i.c.v. injection of 3 mg NPY was administered. Control animals received an ip injection of methylcellulose vehicle. Thirty minutes later, animals received NPY (3 mg). A second group received ip 1 mpk of SCH 39166 and 30 minutes later received 3 mg NPY. A third group of animals received ip 3 mpk of SCH 39166 and 30 minutes later received 3 mg NPY. Food intake was measured 2 hours, 4 hours, and 24 hours after NPY administration. Animals that received 3 mpk of SCH 39166 as a pretreatment showed a significant reduction in food intake 2 hours after NPY administration.

Example 6

A multicenter, double-blind, randomized, controlled trial was conducted in approximately 160 cocaine-dependent patients who received daily doses of 10 mg, 25 mg, or 100 mg of SCH 39166 or placebo for eight weeks. While the study did not demonstrate efficacy of SCH 39166 in reducing cocaine use, it did demonstrate that SCH 39166 was effective in reducing weight, alcohol consumption, and tobacco smoking.

Table 1 shows the number of patients receiving placebo or the indicated dose of SCH 39166 for 28 days - 25 days. Body Mass Index (BMI) and weight of patients were measured at the beginning and end of the study, BMI is determined as weight ( ^kg ) by height (meters). Patients with a BMI of 29.0 to 24.9 are considered normal weight, while a BMI above 25.0 is considered overweight.

Table 1A shows the percentage of patients in each category who lost at least 5 pounds of weight. Table 1B shows the percentage of patients with an initial BMI of 22 or less and the percentage of patients with a BMI of at least 26 who lost at least 1 pound of BMI. From these tables, it can be seen that SCH 39166, especially at a dose of 100 mg/day, was effective primarily in reducing weight in obese subjects, i.e., BMI 26 or greater.

• · ··· ·

ΙΟ ·♦ ···· • ·

Table 1Α

Effects of ecopipam (“ecopipam”) on body weight (Cocaine dependent patients who completed > 28 days of treatment)

Treatment Baseline BMI Weight Change (pounds) Patients with weight loss > 5 pounds Placebo 34 25.5 +2.3 15% 10mg 30 25.2 -1.4 27% 25 mg 32 25.5 -0.9 22% 100mg 29 26.3 -3.3 45%

Table 1B

Treatment n= Patients with weight loss > 1BMI Initial BMi p. 22 Initial BMI ^26 Placebo 34 3/8 (38%) 3/13 (23%) 10mg 30 2/9 (22%) 2/10 (20%) 25 mg 32 2/10(20%) 4/13 (30%) 100mg 29 1/6 (17%) 10/14 (71%)

The D1/ _D5 antagonists or partial D1/ _D5 agonists of the present invention can be used alone in the treatment of food cravings or in combination with behavioral therapy; a weight loss program; with other CNS agents described herein, particularly anti-obesity agents, which include beta 3 agonists, lipase inhibitors such as orlisate, NPY agonists and antagonists, 5HT2c receptor agonists, glucagon-like peptide 1, melanocortin peptides, cholecystokinin, corticotropin-releasing factor, leptin mimics and blockers, and nicotinic agonists. Suitable beta 3 agonists include:

BMS 196,085, which has the chemical name [R»(R*,R*)]’[4»[2-[[2-(3-chlorophenyl)-1-2-hydroxyethylamino]propyl]phenoxy]methanesulfinic acid; and

SR 58611A, which has the chemical name [R-(R*,S*)H[7]I2-{3-chlorophenyl)-2-hydroxyethynamino]5,6,7,8-tetrahydro-2naphthalenyl-3oxy]ethanoic acid ethyl ester hydrochloride. The structures of these compounds are shown in Figure 15.

• · φφφφ •Φ φφφφ

The DJDs antagonists or D1/D5 partial agonists of the present invention may be used in combination with other agents that have been shown to alter food intake or craving, including sibutramine, fluoxetine, flenfluramine and analogs, amphetamine and analogs, phenetramine, diethylpropion, and mazindoline.

Table 2 shows the reduction in alcohol consumption in patients measured in days without any alcohol consumption,

Table 2

SCH 39166 Dosage (mg) % of patients who did not drink alcohol for at least 1 day % of patients who did not drink alcohol for at least 3 days 0 (placebo) 35 29 10 43 23 25 41 31 100 59 ,—j 43

The D 1 /D ₅ antagonists or partial agonists of the present invention can be used alone in the treatment of alcohol craving or in combination with behavioral treatments and/or other CMS agents described herein, particularly alcohol antagonist drugs.

Table 3 shows that low doses of SCH 39166 were also effective in reducing cigarette smoking.

Table 3

SCH 39166 Dosage (mg) % of patients at least 1 day since last cigarette % of patients at least 3 days since last cigarette 0 32 3 10 57 27 25 53 19 100 38 17

The D1/ _D2 antagonists or D2/D3 partial agonists of the present invention can be used alone to treat nicotine cravings or in combination with behavioral treatments, smoking cessation programs, nicotine replacement therapies such as patches, and

9«· chewing gum, alone or in combination with other CNS agents described herein, especially buspirone and buproprolone.

The compositions of the present invention may be administered alone or in combination with other specified compositions, including:

A. anti-obesity agents including beta 3 agonists, sibutramine, lipase inhibitors such as orlistat, NPY agonists and antagonists, 5HT-2c receptor agonists, glucagon-like peptide 1, melanocortin peptides, cholecystokinin, corticotropin-releasing factor, leptin mimics and blockers, and nicotinic agonists;

S, serotonin receptor agonists such as buspirone, gepirone and ipsapirone or serotonin receptor antagonists such as ritanserin, ketanserin, ondansetron, granisetron, sumttriptan, rizatriptan and eletriptan;

C. antipsychotic drugs such as haloperidol, flupenthixol, chlorpromazine and anxiolytics such as diazepam, lorazepam, triazoiam alprazolam and buspirone;

D. antidepressant drugs such as desipramine, imipramine, amitriptyline, clomipramine, fluoxetine, fluvoxamine, paroxetine, sertraline, buproprion and citalopram;

E. dopaminergic antagonists such as bromocripfine, amantadine;

F. anticonvulsants and mood stabilizers such as carbamazepine, phenytoin, lithium, valproic acid, vigabatrin, iamotrigine, tiabagin, azonisamide;

G. cocaine-like agonists such as mazindol, methylphenidate;

H. cocaine catalytic antibodies; and

I. alcohol and opiate antagonist drugs such as disulfiram, acamprosate, and naltrexone.

The use of the DJD* antagonists or partial agonists of the present invention in combination with the other CNS agents noted above may allow lower doses of each agent to be used, thereby providing increased efficacy while reducing side effects.

Suitable D 5 /D ₅ antagonist agents are SCH 39166, SCH 23390 NCC22-0010 and BTS-73-947. A suitable partial D ₅ /D ₅ agonist agent is (+)SKF 38393.

Since the present invention in certain embodiments may involve the administration of a combination of two agents, the agents may be administered together simultaneously or sequentially or in a single pharmaceutical composition. When the agents are administered separately, the number of doses of each agent administered per day may not necessarily be the same, e.g., if one agent has a longer duration of activity, it will therefore be administered less frequently. The compositions may be prepared using conventional pharmaceutical carriers and excipients and using conventional techniques. The compositions may be administered in a conventional oral or parenteral form such as a capsule, tablet, powder, wafer, suspension or solution. When a CNS agent is administered in conjunction with a D1/ _D5 antagonist or a D1/D5 partial agonist, the CNS agent will generally be administered within the known dosage ranges for that agent. The precise dosage administered will be determined by the attending physician and will depend on the strength of the agent administered, the age, weight, condition and response of the patient.

The compositions may be administered to a mammal by any route of administration which will provide the required concentration of the □·,/□? antagonist or partial agonist of OfD _s . When the medicament is administered orally by capsule or tablet, the daily dosage will be in the range of from 0.1 mg/kg per day to 500 mg/kg per day, more suitably from 0.1 mg/kg to 150 mg/kg per day and most preferably from 0.1 mg/kg to 10 mg/kg per day. The compositions are preferably administered 1 to 3 times per day.

The SCH 39166 tablet may have the following composition, suitable: although other compositions are Components 5mg 25 mg 100mg Core SCH 39166 5.0 25.0 100.0 Laciosis NF Monohydrate 114.0 94.0 79.4 very fine powder sodium starch glycolate NF 6.0 6.0 8.0 Povidone USP (K29/32) 4.0 4.0 10.0 Magnesium sulfate 1.0 1.0 2.0 Purified water USP/EP (evaporates) (it evaporates). (evaporates) Weight of the tablet core 130 mg 130 mg 200mg

The tablet may be coated by standard techniques using any approved colorant. It is also contemplated that sustained release of the composition could also be utilized to administer the composition over a given period of time.

Since the present invention may involve separate administration of two compositions, the present invention also relates to combining separate pharmaceutical compositions.

9999 99 9 9

9 9 9 9 9 9

9 9 9 9 9 9

9 9 9 9 9 9 9

9 9 9 9 9 9 · ·· ** means! in the form of a kit. The kit will suitably include instructions for administering the separate means.

While the present invention has been described in connection with the specific embodiments set forth above, many alternatives, modifications, and variations will therefore be apparent to one skilled in the art. All such alternatives, modifications, and variations are intended to be within the spirit and scope of the present invention.

Claims (17)

PATENT CLAIMS Use of a DVDs antagonist, Οχ / Ds partial agonist, or mixtures thereof, in the manufacture of a medicament for reducing a food or addictive drug need in a mammal. Use according to claim 1, wherein the D1 / D5 antagonist or D1 / D5 partial agonist is administered at a daily dose ranging from 0.01 mg / kg to 500 mg / kg, Use according to claim 1 or 2, wherein the addictive substance is cocaine, amphetamine, nicotine, opiates, tobacco or alcohol. Use according to claims 1 to 3, wherein the D 1 / D 1 antagonist is SCH 39166, SCH 23390, BTS-73-947, NCC-22-0010, JHS-271, JHS-198, JHS-136, or A 69024 and the D 2 / D 2 partial agonist is SKF 38393. Use according to any one of claims 1 to 4, wherein the DVDr antagonist is SCH 39166. 6. Use of Dt / D antagonist? or a DVD ₅ partial agonist in combination with one or more means selected from the following classes for the preparation of a medicament for reducing a food or addictive drug need in a mammal: A. anti-obesity agents; B. 5-hydroxytriptamine receptor agonists and antagonists; C. antipsychotics / anxiolytics; D. antidepressants; E. dopaminergic agonists; F. anticonvulsant / mood stimulants; G. cocaine-like agonists; H. cocaine catalytic antibodies; and i. alcohol and opiate antagonist drugs. The use of claim 6, wherein the D7D ₅ antagonist is selected from SCH 39166, SCH 23390, BTS-73-947, NCC-22-0010, JHS-271, JHS-198, JHS-136, or A 69024. 8. Apply! according to claim 7, wherein the D 1 / D 5 antagonist is SCH 39166. Use of SCH 39166 for the preparation of a medicament to reduce food needs in mammals. Use of SCH 39166 for the preparation of a medicament for reducing nicotine needs in a mammal. An assembly for reducing food and addictive substance needs comprising D 1 / D 5 antagonists or a D 2 D 6 partial agonist in combination with one or more means selected from the following classes; A. anti-obesity agents: B. 5-hydroxytriptamine receptor agonists and antagonists; C. antipsychotics / anxiolytics; D. antidepressants; E. dopaminergic agonists; F. anticonvulsant / mood stimulants; G. cocaine-like agonists; H. cocaine catalytic antibodies; and I. alcohol and opiate antagonist drugs. The kit of claim 10, wherein the Di / D _s antagonist is SCH 39166. Use of SCH 39166 in combination with an anti-obesity agent for the preparation of a medicament to reduce food needs in a mammal. Use according to claim 13, wherein the anti-obesity agent is selected from beta 3 agonists, sibutramine, iipase inhibitors, adonists and NPY antagonists, 5HT- _2C receptor agonists, giucagon-like peptide 1, melanocortin peptides, cholecysiokinin, corticiropine release factor, leptin mimic means and biocators, fat absorbing biocators and nicotinic agonists. The use of claim 14, wherein the iipase inhibitor is oriistat. Use according to claim 14, wherein the anti-obesity agent is sibutramine. The use of claim 14, wherein the anti-obesity agent is a beta 3 agonist.