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 ( þ )butaclamol. MEASUREMENTS: Colonic temperature and food intake at room temperature (21 AE 1 C), thermoregulatory behavioural response, operant responding for exogenous heat at 7 8 C and oxygen consumption at thermoneutrality (29 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 a 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 b-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 a 2 -adrenoceptor antagonist, RS79948 (1 mg=kg, p.o.), and the D2=D1 receptor antagonist, ( þ )butaclamol (200 mg=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 7 8 C to maintain body temperature, and this effect was not affected by the D2=D1 receptor antagonist ( þ )butaclamol (100 mg=kg 71 , i.p.). The hypophagia induced by M2 (10 mg=kg) measured up to 24 h was partially antagonized by the a 1 -adrenoceptor antagonist, prazosin, whereas metergoline, RS79948, propranolol and ( þ )butaclamol had no effect on M2-induced hypophagia. CONCLUSION: It is concluded that 5-HT, a 1 -and b 3 -adrenoceptors are involved in the induction of thermogenesis by M2, whereas the hypophagic effect is mainly mediated via a 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).

Brown adipose tissue and its therapeutic potential

“…Stimulation of BAT via the sympathetic nervous system is thought to contribute to the weight loss effects from appetite-reducing drugs such as sibutramine or ephedrine [112][113][114]. These centrally acting drugs can cause serious side effects such as cardiac arrhythmias or hypertension, however, and have therefore been withdrawn from the market.…”

Locomotor and peripheral effects of sibutramine modulated by 5-HT2 receptors

“…Sibutramine has been described as an anti-obesity drug with the ability to inhibit serotonin (5-HT), noradrenaline, and dopamine re-uptake, but without affinity to histamine and muscarinic receptors (Bray et al 1996;McNeely and Goa 1998;Nisoli and Carruba 2003). It has been proposed that the in vivo effects of sibutramine are mediated by the inhibition of the reuptake of 5-HT and noradrenaline in the central nervous system, thus affecting the energy balance (Gundlah et al 1997;Jackson et al 1997;Liu et al 2002;Strack et al 2002). Sibutramine increases the expenditure of energy and is based on a synergistic interaction between enhanced noradrenaline and the 5-HT function (Connoley et al 1999;Heal et al 1998a).…”

Obesity: Development, Epidemiology, Factors Affecting, Quantity, Health Hazards, Management and Natural Treatment-a Review

“…It is a dual monoamine form, there arenor-adrenaline and serotonin (5-Hydroxytryptamine) reuptake inhibitor [92][93][94] noradrenaline in the nerve ending of central nervous system(CNS), and this action has anorexigenic and satiety effects, effective in improving metabolic syndrome parameters such as fasting glucose, triglycerides and HDL [95]. The sibutramine is contraindicated in patients with a history of cardiovascular disease, including coronary artery disease, stroke or transient ischemic attack, cardiac arrhythmia, congestive heart failure, peripheral arterial disease, or uncontrolled hypertension [96].…”