Mechanism of the thermogenic effect of Metabolite 2 (BTS 54 505), a major pharmacologically active metabolite of the novel anti-obesity drug, sibutramine.

Abstract

OBJECTIVE:

To investigate the pharmacological mechanisms underlying the induction of thermogenesis by Metabolite 2 (M2; BTS 54 505), a major pharmacologically active metabolite of the anti-obesity drug, sibutramine.

DESIGN:

Adult female Wistar rats were treated with M2 or vehicle, with or without various monoamine receptor antagonists, prazosin, RS79948, metergoline, propranolol and (+)butaclamol.

MEASUREMENTS:

Colonic temperature and food intake at room temperature (21+/-1 degrees C), thermoregulatory behavioural response, operant responding for exogenous heat at -8 degrees C and oxygen consumption at thermoneutrality (29 degrees C).

RESULTS:

M2 (10 mg/kg, p.o.) significantly increased colonic temperature during the 4.5 h period following drug administration. This effect was abolished by the non-selective 5-HT receptor antagonist, metergoline (1 mg/kg, p.o.), and alpha(1)-adrenoceptor antagonist, prazosin (1 mg/kg, p.o.), measured at 1.5-2.5 h post-M2 administration, and was partially antagonized by each antagonist at 3.5-4.5 h. The non-selective beta-adrenoceptor antagonist, propranolol (1 mg/kg, p.o.), had no effect on the M2-induced increase in colonic temperature, whereas at 20 mg/kg (p.o.), propranolol partially inhibited the effect of M2 on colonic temperature. By contrast, the selective alpha(2)-adrenoceptor antagonist, RS79948 (1 mg/kg, p.o.), and the D2/D1 receptor antagonist, (+)butaclamol (200 micro g/kg, p.o.), did not alter the effect of M2 on colonic temperature. In the thermoregulatory study, M2 (10 mg/kg, i.p.)-treated rats required significantly less radiant heat at -8 degrees C to maintain body temperature, and this effect was not affected by the D2/D1 receptor antagonist (+)butaclamol (100 micro g/kg(-1), i.p.). The hypophagia induced by M2 (10 mg/kg) measured up to 24 h was partially antagonized by the alpha(1)-adrenoceptor antagonist, prazosin, whereas metergoline, RS79948, propranolol and (+)butaclamol had no effect on M2-induced hypophagia.

CONCLUSION:

It is concluded that 5-HT, alpha(1)- and beta(3)-adrenoceptors are involved in the induction of thermogenesis by M2, whereas the hypophagic effect is mainly mediated via alpha(1)-adrenoceptors. These findings are consistent with M2 increasing 5-HT and noradrenaline tone via potent reuptake inhibition which subsequently results in increased efferent sympathetic activity to brown adipose tissue (BAT).

• Authors: Y-L Liu, D J Heal, M J Stock
• Journal: International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity (Int J Obes Relat Metab Disord) Vol. 26 Issue 9 Pg. 1245-53 (Sep 2002) England
• PMID: 12187403 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic alpha-Antagonists
• Adrenergic beta-Antagonists
• Anti-Obesity Agents
• Appetite Depressants
• Cyclobutanes
• Dopamine Antagonists
• Serotonin Antagonists
• BTS 54 505
• sibutramine

Topics

• Adrenergic alpha-Antagonists (pharmacology)
• Adrenergic beta-Antagonists (pharmacology)
• Animals
• Anti-Obesity Agents (pharmacology, therapeutic use)
• Appetite Depressants (metabolism)
• Behavior, Animal (drug effects)
• Body Temperature (drug effects)
• Body Temperature Regulation (drug effects)
• Colon (drug effects)
• Cyclobutanes (metabolism, pharmacology, therapeutic use)
• Dopamine Antagonists (pharmacology)
• Eating (drug effects)
• Female
• Obesity (drug therapy)
• Rats
• Rats, Wistar
• Serotonin Antagonists (pharmacology)
• Thermogenesis (drug effects)
• Time Factors