WO1990003168A1

WO1990003168A1 - Method for modifying feeding behavior

Info

Publication number: WO1990003168A1
Application number: PCT/US1989/003604
Authority: WO
Inventors: Jack David Barchas; Robert Scott Bitner; Glen Raymond Elliott; Theresa Marion Gadbois; Stephen Scott Bowersox
Original assignee: Neurex Corporation
Priority date: 1988-09-19
Filing date: 1989-08-21
Publication date: 1990-04-05
Also published as: AU4079389A

Abstract

Immediate and long term reduction in food intake is achieved by administering 1,2,3,4-tetra-hydro-beta-carboline (THBC) at dosages below 25 mg/Kg/day. At lower dosages, THBC alters macro-nutrient preferences, and is thus useful for reducing substance craving behavior, for example the carbohydrate craving experienced by subjects suffering from bulimia.

Description

METHOD FOR MODIFYING FEEDING BEHAVIOR

Description

Technical Field

This invention is in the field of chemistry and appetite control. More specifically, this inven- tion relates to methods for suppressing appetite and/ or for altering a subject's macronutrient prefer¬ ences, and compounds useful therefor.

Background of the Invention The high prevalence of obesity in the

United States attests to the general failure of existing medical treatments to adequately manage the problem. The limited efficacy of existing anorectic agents when measured against possible risk factors inherent in their use currently precludes them as treatments of choice for the management of obesity. However, there is a growing awareness among both patients and the medical community that obesity is a disease that requires aggressive medical interven- tion. Thus, new anti-obesity agents with signifi¬ cantly improved performance characteristics are likely to be well-received in the future.

The most commonly used weight control agents available without prescription are generally adrenergic stimulants such as phenylpropanola ine and phenethylamine derivatives. Although effective appetite inhibitors, adrenergic agents produce numer¬ ous untoward side effects, such as nervousness, irritability, insomnia, dizziness, tachycardia, pal¬ pitations, hypertension, and the like. These side effects may be severe enough to require cessation of treatment. Kopf, DE 3,430,389, disclosed weight- reduction by administering a combination of an adren¬ ergic agent with a benzodiazepin sedative. The actual safety of such adrenergic agents is question- able, particularly in view of the 20-30% of the U.S. population suffering from hypertension. Non-stim¬ ulant anorectic agents produce few untoward side effects, but may interfere with patient compliance in exercise programs, as they generally produce drowsi- ness and CNS depression. Thus, it is apparent that none of the current anti-obesity pharmacotherapies available are particularly satisfactory.

Although the nosology of obesity and related eating disorders is not currently well defined, with its development and broadening accept¬ ance grows the need to design safe and effective pharmacotherapies. One area of particular need is the development of drugs that selectively inhibit appetite for specific acronutrients. Anorectic agents of this type would be beneficial to indi¬ viduals who preferentially overeat particular types of food, such as obese patients who cannot control their craving for carbohydrate-rich snacks, or patients with seasonal affective disorders who become depressed and crave carbohydrates during the Fall and Winter. Wurtman et al., U.S. Pat. No. 4,452,815 and 4,309,445 disclosed that limited doses of the phen- ethyla ine derivative fenfluramine inhibited sub¬ jects' appetite for carbohydrates without affecting their global appetite. Fenfluramine is a known anorectic agent, having the chemical name N-ethyl-2- ( 3-trifluoromethyl)-1-methylphenethylamine.

The present invention relates to a novel method of use for 1,2, 3,4-tetrahydro-beta-carboline ( 1,2,3,4-tetrahydro-9H-pyrido[3-4b]indole) . The com¬ pound possesses the following structural formula:

Tetrahydro-beta-carboline (THBC) has a variety of pharmacological actions and has been variously evaluated as a cholinesterase inhibitor, sedative/hypnotic, analgesic, and psychotomimetic . It competes with low affinity for brain tryptamine, imipramine, 5-hydroxytryptamine (5-HT), and spiperone binding sites, enhances depolarization-induced 5-HT efflux from brain slices, inhibits 5-HT uptake in brain synaptosomes , and inhibits 5-HT oxidative de- amination. It has been found naturally ocurring in mammalian brain tissue. When THBC is administered to laboratory animals, it suppresses locomotion, exploratory activity, and conflict behavior, impairs performance on operantly conditioned learning and memory tasks, reduces seizure susceptibility, pro¬ longs barbiturate sedation, and antagonizes specific drug-induced stereotypies . hen given in high doses, THBC induces a characteristic behavioral syndrome characterized by hyperactivity, forepaw treading, body weaving, and circling (Airaksinen et al, Med Biol (1981) 5£:190-211). Atkinson, GB 1,183,219 dis- closes its use as an analgesic. THBC has been dis¬ closed to reduce motor activity, induce apparent anxiety, and increase voluntary ethanol consumption in rats when administered intraventricularly (P. Huttunen et al, Pharmacol Biochem & Behav (1986) _24_:1733-38) . Physiological actions of THBC include effects on endocrine secretory patterns and body tem¬ perature. Systemic administration in rodents produces a dose-dependent elevation of plasma pro- lactin levels, decreased serum luteinizing hormone levels, and elevated plasma corticosterone. THBC elicits significant hypothermia when administered to rats parentally in doses of 6.25 mg/Kg or greater (H. Rommelspacher et al, Naunyn-Schmiedeberq's Arch Pharmacol (1977) 298:83-91) ■ It is also known that daily oral adminis¬ tration of THBC produces temporary dose-related dec¬ rements in food and fluid intake in rats. Animals that receive average daily amounts of THBC in excess of 49 g/kg show significant reductions in food intake after two consecutive days of treatment; tol¬ erance develops, and food consumption returns to nor¬ mal by the twelfth treatment day. Smaller daily doses (less than 30 mg/kg) do not significantly alter appetite (Rommelspacher; Airaksinen et al, Med Biol (1981) 59_^:190-211). It is noteworthy that in Rommel¬ spacher's report, 6 out of the 24 animals receiving 49 mg/Kg/day or greater died.

To exploit the utility of THBC as an anorectic agent, it is desirable to develop a method of reducing appetite and producing weight loss which 1) produces immediate and significant reductions in food intake, 2) produces minimal side-effects, and 3) does not lead to the early development of drug toler¬ ance. Because obesity may frequently result from over-consumption of high-carbohydrate foods, it is additionally desirable to develop a method that spe- cifically inhibits appetite for carbohydrates. Such a method would also be useful for treating specific eating disorders, such as bulimia, that are charac¬ terized by abnormally intense cravings for carbo- hydrates. Such-an effect would additionally be use¬ ful for treating individuals with seasonal affective disorders, who become depressed at specific times of the year and crave carbohydrates. Finally, such an effect would be more generally useful for treating individuals with substance cravings per se.

Summary of the Invention

One object of the present invention is to provide a method for reducing food intake by adminis- tering THBC, without potentiating undesired effects such as abnormal motor behaviors and tolerance that normally develop with THBC treatment. The method comprises the administration of an effective amount of THBC either alone or more or less simultaneously with the administration of an amount of mild stimulant such as caffeine, which itself would not produce the desired anorectic effect. This method is useful in that lower amounts of THBC may be adminis¬ tered to produce immediate, significant, and persist- ent reductions in food intake with fewer dose-related side effects.

It is a further object of this invention to provide a method for selectively reducing appetite for carbohydrates. The present invention provides a novel method of modifying food preferences and inducing anorexia in animals which comprises the administra¬ tion of safe and effective amounts of THBC either alone or in combination with a mild stimulant such as caffeine. The invention is based on the discovery that (1) low doses of THBC selectively suppress appetite for high-carbohydrate-containing foodstuffs and (2 ) at higher doses, THBC produces immediate and significant reductions in total food intake without leading to the early development of tolerance. Phar- maceutical formulations useful in the practice of the method are additionally provided.

Modes of Carrying Out The Invention

A. Definitions

The terms "1,2,3,4-tetrahydrobetacarbo- line," "tryptoline, " and "THBC" are synonymous and include not only the free base but also pharmaceuti¬ cally acceptable acid addition salts thereof. Suit- able acid addition salts may be formed using either mineral or organic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, fumaric acid, tar- taric acid, acetic acid, benzoic acid, valeric acid, and the like. Acid addition salts may be conven- iently prepared by treating a solution or suspension of the free base in solvent with the desired acid, and purifying the resulting salt by conventional crystallization techniques .

The term "anorectically effective amount" as used herein refers to an amount of THBC sufficient to significantly reduce food consumption in a mammal. The precise amount of THBC may vary with the age and species of the mammal, and with the presence or ab¬ sence of specific appetite disorders, and thus may not be stated precisely. However, such amounts may be determined by one of ordinary skill in the art, using standard, routine methods. As a general guide, an anorectically effective amount for humans will range from about 0.5 mg/Kg/day to about 25 mg/Kg/day, and in general will not exceed about 30 mg/Kg/day. The term "carbohydrate suppression effec¬ tive amount" refers to that amount of THBC which sig¬ nificantly alters the subject mammal's appetite for carbohydrate. A carbohydrate suppression effective amount will generally range from about 0.5 mg/Kg/day to about 8 mg/Kg/day.

The amount of THBC effective for reducing substance cravings will also vary depending upon the type and severity of the cravings, the age and condi- tion of the subject, and other factors. Thus, an exact dosage cannot be specified. However, as a gen¬ eral guide, this effective amount will generally range from about 0.5 mg/Kg/day to about 8 mg/Kg/day. "Substance cravings" refers to abnormal or unnatural appetite for foodstuffs or other substances, which are common aspects of appetite disorders. For example, bulimia is often characterized or accom¬ panied by an unusual craving for carbohydrates . Another appetite disorder characterized by substance cravings is pica, in which the subject craves non- edible substances, such as ashes, sand, etc. Sub¬ stance cravings also encompass chemical addiction or psychological dependency, such as alcohol, tobacco, and opiate addiction. In addition to the biochemical basis that such addictions may engender, a psycho¬ logical disposition often exists either as cause or result of the addiction. We believe that such psychological basis must also be treated in order to effect a complete cure from addiction. The term "mild stimulant" as used herein refers to a pharmaceutically acceptable compound which has moderate to slight CNS stimulatory activ¬ ity, which are useful for counteracting mild motor depression. Mild stimulants include, without limita- tion, caffeine, dyphylline, oxtryphylline, theophyl- line, deanol acetamidobenzoate, methylphenidate hydrochloride, and the like, Caffeine is presently preferred.

B. General Method

THBC is commercially available (e.g., from Aldrich Chemical Co., Milwaukee, WI) . Alternatively, THBC may be prepared by any of several conventional methods. One synthetic pathway is illustrated below. In summary, tryptamine (which is commercially avail¬ able) is reacted with glyoxylic acid at pH 4 to form 1-carboxy-l,2,3,4-tetrahydrobetacarboline, which is then decarboxylated by heating under acid catalysis to form 1,2,3,4-tetrahydrobetacarboline (THBC).

Pharmaceutical compositions containing THBC, preferably as an acid addition salt, may con- tain one or more pharmaceutical carriers. When the carrier serves as a diluent, it may be solid, semi- solid, or liquid material acting as a vehicle, excip- ient, or medium for the active ingredient. Pharma¬ ceutical unit dosage forms may be prepared for admin- istration by any of several routes including, but not limited to, oral and parenteral (especially by intra- muscular and intravenous injection, or by subcutane¬ ous implant or transdermal administration) . Repre¬ sentative of such forms are tablets, soft and hard gelatin capsules, powders, lozenges, chewing gums, emulsions, suspensions, syrups, solutions, sterile injectible solutions, and sterile packaged .powders . Compositions containing THBC may be formulated by procedures known in the art so as to provide rapid, sustained, or delayed release of any or all of the compounds after administration.

Solid pharmaceutical excipients such as magnesium stearate, calcium carbonate, silica, starch, sugar, talc, and the like may be used with other conventional pharmaceutical adjuvants including fillers, lubricants, wetting agents, preserving agents, disintegrating agents, flavoring agents, and binders such as gelatin, gum arabic, cellulose, methylcellulose, and the like, to form admixtures which may be used as such or may be tabulated, encapsulated, or prepared in other suitable forms as noted above. The preferred liquid diluent is physio¬ logically normal saline. A general description of formulation is given in "Remington's Pharmaceutical Sciences" (Mack Pub. Co.) . THBC administered either alone or in combi¬ nation with caffeine produces significant, long-last¬ ing reduction in food intake when administered to mammals within 8 hours prior to meal presentation. Contrary to the prior art, we have found that THBC administered in doses of 0.5 to 25 mg/Kg/day is ef¬ fective in reducing appetite without inducing tol¬ erance, or other side effects reported for oral administration of 49 mg/kg THBC. The depressive effect on motor behavior that THBC may cause can be avoided by coadministration of a reasonable amount of a mild stimulant, such as caffeine. Further, we have found that doses within the lower end of the range (8 mg/Kg/day or less) are effective for specifically reducing appetite for carbohydrate-rich diets .

C. Examples

The examples presented below are provided as a further guide to the practitioner of ordinary skill in the art, and are not to be construed as lim¬ iting the invention in any way.

Example 1 (Anorectic Effect) The use of THBC to produce immediate, sig¬ nificant reductions in food intake is illustrated by the following experiment in which the compound was administered intraperitoneally at a dose of 25 mg/kg to groups of 10 rats each. The following protocol was used:

Adult male rats (250 to 300 g) were ac- climated to laboratory conditions for a period of five days during which they were allowed unrestricted access to food (Ralston-Purina #5001M: 23.4% pro¬ tein, 4.5% fat, 49% carbohydrate) and water. All animals were housed in individual cages. The animal facility was maintained on a 12:12 hr light-dark cycle at 22°C.

Animals were matched by body weight and mean daily food intake and assigned to 6 groups. Food jars were removed at 09:00 hr. Twenty-four hours later, rats were administered either normal saline or saline containing THBC (25 mg/kg). Pre- weighed food jars containing meal were provided at post-injection time points given in Table 1. These were weighed after one hour and food consumption was calculated. ' Animals were permitted ad libitum access to tap water throughout the experiment. As shown in Table 1, significant reductions in food intake occurred during the first hour after drug administration. Appetite was significantly at¬ tenuated up to 8 hours post-injection.

Table I (Duration of Activity)

Group Test Food Intake/ % Control Period 1 hr (gm) (hr)

Saline controls (2) evaluated at 0, 2 , 4 , 8, and 24 hours.

(b) mean + SEM for all control measurements. All control measurements were statistically equiva¬ lent .

(c) control vs experimental, p<0.01 by two-tailed Student's t-test . Values are means + SEM.

The results demonstrate that at low (25 mg/ Kg) dosages, an immediate and long-lasting anorectic effect is obtained.

Example 2 (Dose Response) Dose ranging studies showed that THBC sig¬ nificantly reduced food intake when administered par- enterally to rats in amounts appreciably lower than 25 mg/kg. Fasted animals were sorted into 5 groups of 12 each by weight and baseline food intake. Each was then given either saline or 5-25 mg/kg THBC, and immediately allowed access to food and water. Cumu¬ lative food intake was measured up to 8 hours post- injection. Doses as low as 5 mg/kg significantly reduced food consumption (Table II).

Table II (Dose Response)

* significant vs contro , p<0.01 by two-tailed Student's t-test. Values are means + SEM.

In the examples given above, THBC was ad¬ ministered parenterally. In clinical usage as an anorectic agent in mammals, particularly humans, the oral route of administration would probably be pre¬ ferred. In the case of intraperitoneal administra¬ tion in rodents, amounts as low as 5 mg/kg of body weight are sufficient to achieve effective sig¬ nificant appetite suppression.

Example 3 (Oral Administration) THBC produces immediate, statistically sig¬ nificant reduction in food intake when administered- by the oral route in doses under 32 mg/Kg. Fasted rats were sorted into 5 groups of 10 each by weight and baseline food intake (Ralston-Purina #5001M) . Each was administered either saline or 8-64 mg/Kg THBC by iήtragastric feeding tube, and immediately given access to food and water. Cumulative food intake in the first hour after drug administration was significantly reduced in animals receiving 32 mg/ Kg THBC. The dose effective to reduce food intake by 50% (ED,-₀) was approximately 53 mg/Kg. The results are shown in Table III

Table III (Dose Response After Oral Administration)

Group Food Intake/Hour Control 100.0%

95.9% 85.7%

67.3%

44.9%

* Statistically significant (p<0.01) by two-tailed Student's t-test Example 4

(THBC with Mild Stimulants) Administration of a mild stimulant with THBC reverses the motor inhibition that may be pro¬ duced by THBC treatment alone. This is illustrated in the following experiment. Adult male rats, ac¬ climated to laboratory conditions as described above (Example 1), were sorted into four groups of four each. Rats were administered saline, THBC, caffeine, or THBC + caffeine by intraperitoneal injection. Locomotor activity was evaluated after 30 minutes by placing each animal in a 20" x 20" test cubicle, the floor of which was cross-hatched in a 5" x 5" grid pattern. Motion was quantified by counting the number of line crossings. The data presented in Table IV below represent the number of line crossings (mean + se ) recorded during a continuous 15-minute observation period.

Table IV (Locomotor Activity)

Group Line Crossings/15 minutes saline 96.5 + 19.3

THBC (25 mg/Kg) 7.8 + 2.6 caffeine (50 mg/Kg) 130.0 + 39.2 THBC + caffeine 27.3 + 12.7* * Statistically significant (p<0.05 by Student's t-test) vs THBC group.

As demonstrated in Table IV, animals that received a combination of THBC and caffeine were sig¬ nificantly more active than those that received THBC alone. These finding illustrate the fact that reduc¬ tions in motor activity produced by THBC can be over¬ come by co-administration of an appropriate amount of a mild CNS stimulant.

Example 5 (Tolerance)

The effect of chronic administration (>20 days) of THBC on food intake was studied as set forth below. Rommelspacher reported that, when THBC was administered at doses of 49 mg/kg/day, food consump¬ tion was only temporarily reduced, returning to pre- drug baseline levels after about 8 days of treatment. In contradistinction to this report, we find that THBC administered in substantially lower doses (25 mg/kg) continues to exhibit anorectic potency even after 26-30 days of treatment. Thus, THBC is ad¬ ditionally useful in the long-term treatment of obes¬ ity and eating disorders in general. The following example illustrates this finding.

Thirty male (Sprague-Dawley) rats were housed under laboratory conditions as described abσve, and adapted to a 6 hour (9:00-15:00 h) daily feeding schedule. Animals were then given intra- peritoneal injections of either normal saline (N=15 rats/group) or THBC (25 mg/kg in saline; N=15 rats/ group) once before food presentation. Cumulative food intake was measured at 1 hour (10:00 -h) and 6 hours (15:00 h) postinjection. Findings are sum¬ marized in the table below. As shown, food intake measures for the THBC group were significantly lower than those for the saline group at all time points.

Table V (Effects of Chronic Treatment)

Food consumption after administration+ 1 Hour 6 Hours Da s Saline THBC Saline THBC

+ values represent mean (+SEM) food consumption per animal in grams over the indicated treatment days, measured for a 1 hr period either 1 or 6 hrs after injection.

* significantly different (p<0.05) from saline con¬ trols by two-tailed Student's t-test.

The results demonstrate that, at the dose level administered, the experimental animals did not develop tolerance to the anorectic effect of THBC. Accordingly, THBC is useful as a long-term therapy for treatment of obesity and similar eating dis¬ orders .

Example 6

(Alteration of Macronutrient Preference)

This example demonstrates alteration of macronutrient preference in rats.

Sixty adult male rats (Sprague-Dawley) were acclimated to laboratory conditions for a period of 10 days, during which they were allowed unrestricted access to food (Ralston-Purina #5001) and water. All subjects were housed in individual cages, and the animal facility maintained on a 12:12 hour light-dark cycle at 24-27°C

Animals were assigned to 6 groups (10 per group) , then allowed to consume one of two iso- caloric, iso-nitrogenous test diets containing either 71% or 23% carbohydrate. Animals were maintained on the test diets for 3 days according to a 6 hour restricted access schedule prior to drug testing. After 3 days, food jars were removed. After an additional 24 hours, rats were administered either saline or THBC ( or 8 mg/Kg body weight), then given immediate access to the test diets. Data listed in Table VI indicate the cumulative amount in grams (mean +_ SEM) of each diet during the subsequent 3 hour period.

Table VI (Modulation of Carbohydrate Consumption)

71% Carbohydrate 23% Carbohydrate Treatment -2 Hr 3 Hr 2 Hr 3 Hr

saline 7.3+0.55 8.6+0.51 7.6+0.56 9.1+0.57

THBC 6.6+0.38 7.9+0.30 6.5+0.41 8.3+0.63 (4 mg/kg) THBC 5.4+0.36* 7.1+0.42* 6.6+0.40 8.0+0.41 (8 mg/kg)

* Statistically significant vs control (p<0.05 by Student's t-test)

The results indicate that animals receiving 8 mg/Kg THBC consumed significantly less of the high carbohydrate diet than did controls, but consumed equivalent quantities of the low carbohydrate diet. Thus, THBC selectively suppresses carbohydrate cravings when administered at doses lower than those effective for global appetite reduction. This demon¬ strates the utility of the present invention as a method of reducing substance cravings per se, insofar as food cravings model clinical syndromes in which there is excessive preoccupation with, or urges for, specific habituating substance (Glassman et al, Science (1984) 226 :864) . Accordingly, this example evidences efficacy in the treatment of alcohol, tobacco, and drug (particularly opiate) addiction.

Claims

WHAT IS CLAIMED:

1. A pharmaceutical composition for treating excessive food consumption and substance cravings, which composition comprises: an effective amount of THBC or a pharmaceu¬ tically acceptable salt thereof; a pharmaceutically acceptable mild stimulant in an amount sufficient to ameliorate CNS depressive effects due to THBC or its pharmaceu¬ tically acceptable salts; and a pharmaceutically acceptable excipient.

2. The composition of claim 1 wherein said mild stimulant comprises caffeine.

3. The composition of claim 2 wherein said THBC or pharmaceutically acceptable salt thereof is present in an amount between about 35 mg and about 1.75 g, as a unit dosage form.

4. Use of THBC for the manufacture of a composition useful for reducing food intake.

5. Use of THBC for the manufacture of a composition useful for suppressing carbohydrate appetite without significant depression of appetite for protein and lipids.

6. Use of THBC for the manufacture of a composition useful for reducing substance cravings.

7. Use of THBC for the manufacture of a composition useful for treating seasonal affective disorder.

8. Use of THBC in combination with a mild stimulant for the manufacture of a composition useful for treating seasonal affective disorder.

9. The use of claim 8 wherein said mild stimulant comprises caffeine.