BTS 54-505 hydrochloride

IC50: 0.066 μM for noradrenaline uptake; 5.1 μM for 5-HT uptake; 0.31 μM for dopamine uptake

Sibutramine HCl (BTS 54-524) is an inhibitor of the reuptake of monoamines with a pharmacological profile in rodents indicative of non-tricyclic putative antidepressant activity. BTS 54-505 is the primary amine metabolite of sibutramine.

In vitro: Simultaneous application of BTS 54-505 with 5-HT resulted in a prolongation of the recovery time from the 5-HT-mediated suppression of discharge activity. BTS 54-505 also prolonged the recovery time from a NA-mediated potentiation of firing. These effects on recovery time are attributed to the inhibition of uptake of both 5-HT and NA by BTS 54-505. The amplitude of the response to 5-HT or NA was unaffected by co-ejection of BTS 54-505 [1].

In vivo: The secondary (BTS 54-354) and primary (BTS 54-505) amine metabolites of sibutramine HCl exhibit similar in vivo pharmacological activity to the parent compound. Thus, each compound displays potent activity in acute behavioural models predictive of antidepressant effects and a comparable ability to inhibit the uptake of monoamines [2].

Clinical trial: Up to now, BTS 54-505 is still in the preclinical development stage.

Reference:
[1] Scott G, Luscombe GP, Mason R.  The effects of BTS 54-505, a metabolite of sibutramine, on monoamine and excitatory amino acid-evoked responses in the rat dorsolateral geniculate nucleus in vivo. Br J Pharmacol. 1994 Jan;111(1):97-102.
[2] Luscombe GP, Hopcroft RH, Thomas PC, Buckett WR.  The contribution of metabolites to the rapid and potent down-regulation of rat cortical beta-adrenoceptors by the putative antidepressant sibutramine hydrochloride. Neuropharmacology. 1989 Feb;28(2):129-34.

Mechanism of the thermogenic effect of Metabolite 2 (BTS 54 505), a major pharmacologically active metabolite of the novel anti-obesity drug, sibutramine.[Pubmed:12187403]

Int J Obes Relat Metab Disord. 2002 Sep;26(9):1245-53.

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).

In vivo criteria to differentiate monoamine reuptake inhibitors from releasing agents: sibutramine is a reuptake inhibitor.[Pubmed:9353373]

J Pharmacol Exp Ther. 1997 Nov;283(2):581-91.

Because monoamine reuptake inhibitors and releasing agents both increase extracellular neurotransmitter levels, establishing in vivo experimental criteria for their classification has been difficult. Using microdialysis in the hypothalamus of unanesthetized rats, we provide evidence that serotonin- (5-HT) selective and nonselective reuptake inhibitors can be distinguished from the 5-HT-releasing agent fenfluramine by four criteria: 1) Systemic fenfluramine produces a much greater increase in 5-HT than the reuptake inhibitors. 2) The 5-HT somatodendritic autoreceptor agonist, (+/-)-8-hydroxy-(dipropylamino)tetralin (8-OH-DPAT), attenuates the increase in 5-HT produced by reuptake inhibitors, but not by fenfluramine. 3) The large increase in 5-HT produced by infusion of reuptake inhibitors into the hypothalamus is attenuated by their systemic administration. However, systemic injection of fenfluramine during its local infusion does not attenuate this increase. 4) Reuptake inhibitor pretreatment attenuates fenfluramine-induced increases in 5-HT. According to these criteria, the in vivo effects of the novel antiobesity drug sibutramine are consistent with its characterization as a 5-HT reuptake inhibitor and not a 5-HT releaser. Thus, sibutramine produced increases in hypothalamic 5-HT similar in magnitude to the effects of the known reuptake inhibitors, and the increase was attenuated by 8-OH-DPAT. Also, sibutramine attenuated fenfluramine-induced 5-HT release. Systemic administration of sibutramine failed to attenuate the increase in 5-HT produced by its local infusion, suggesting that this criterion is not applicable to compounds with low affinity for the 5-HT transporter.

The contribution of metabolites to the rapid and potent down-regulation of rat cortical beta-adrenoceptors by the putative antidepressant sibutramine hydrochloride.[Pubmed:2541365]

Neuropharmacology. 1989 Feb;28(2):129-34.

Sibutramine HCl is an inhibitor of the reuptake of monoamines with a pharmacological profile in rodents indicative of antidepressant activity. The secondary (BTS 54 354) and primary (BTS 54 505) amine metabolites of the tertiary amine sibutramine HCl exhibit similar in vivo pharmacological activity to the parent compound. Thus, each compound displays potent activity in acute behavioural models predictive of antidepressant effects and a comparable ability to inhibit the uptake of monoamines in vivo. In addition, BTS 54 354 and BTS 54 505 induce an equally rapid and potent down-regulation of cortical beta-adrenoceptors in the rat as sibutramine HCl. The secondary and primary amines are, however, considerably more active than sibutramine HCl as inhibitors of the uptake of noradrenaline, dopamine and 5-hydroxytryptamine in vitro. The potent inhibition of the reuptake of noradrenaline by the secondary and primary amine metabolites probably contributes to the rapid and potent down-regulation of beta-adrenoceptors in the rat, induced by the putative antidepressant sibutramine HCl.