BTS 54 524—an Approach to a Rapidly Acting Antidepressant

Buckett, W. R.; Luscombe, Graham; Thomas, P C

doi:10.1007/978-1-349-09506-3_13

Cited by 5 publications

(2 citation statements)

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“…21 The functional expression of the 5-HT receptors in the hypothalamus provides further evidence for a serotonergic involvement in thermogenesis, as the hypothalamus has long been implicated in the control of feeding and energy balance. 22 As neither M2, nor its parent compound, sibutramine, exhibits affinity for 5-HT receptors 23 (Cheetham, personal communication), indirect activation of 5-HT receptors subsequent to potent inhibition of 5-HT reuptake is predicted to be partly responsible for the thermogenic property of M2. Metergoline is a non-selective 5-HT receptor antagonist which has high affinity for 5-HT 1 and 5-HT 2 receptors.…”

Section: Discussionmentioning

confidence: 99%

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

Heal

2002

Int J Obes

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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).

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Section: Discussionmentioning

confidence: 99%

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

Heal

2002

Int J Obes

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“…In models indicative of potential antidepressant activity, sibutramine potently counteracted the behavioural effects of reserpine and downregulated cortical P-adrenoceptors after only three days treatment (Buckett et al, 1988a). This profile is characteristic of monoamine reuptake inhibitors, but sibutramine is a relatively weak inhibitor of noradrenaline (NA), 5-hydroxytryptamine (5-HT) and dopamine uptake in vitro (Cheetham et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

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

Scott

Luscombe²,

Mason

1994

British J Pharmacology

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1 The effects of BTS 54 505, the primary amine metabolite of the non-tricyclic putative antidepressant sibutramine, on the responses evoked by visual stimulation and ionophoretic application of noradrenaline (NA), 5-hydroxytryptamine (5-HT) and excitatory amino acids (EAAs) in the rat dorsolateral geniculate nucleus (dLGN) have been investigated. 2 Ionophoretic application of 5-HT to dLGN neurones attenuated visually-evoked (n = 46), NMDAevoked (n = 21) and AMPA-evoked responses (n = 21), while ionophoretic application of NA potentiated visually-evoked activity in these cells (n = 27). 3 Simultaneous application of BTS 54 505 with 5-HT (over 120 s) resulted in a prolongation of the recovery time (i.e. the period required by a neurone to recover by 50%, RT50) from the 5-HT-mediated suppression of discharge activity (,275% increase in RTm,). BTS 54 505 also prolonged the recovery time from a NA-mediated potentiation of firing (;450% increase in RTm). 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. 4 Ionophoretic application of N-methyl-D-aspartate (NMDA) produced a current-dependent increase in neuronal firing, as did application of the non-N4DA receptor agonist a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). A simultaneous 120 s application of BTS 54 505 inhibited the NMDA response in all cells studied (mean EDm = 16 ± 5 nA) but had no effect on AMPA-evoked activity in the majority of the same cells (n = 15/21). 5 Short 10 s applications of BTS 54 505, at ejecting currents () 30 nA) that attenuated NMDA-evoked activity in all cells studied, had no effect on either response amplitude or recovery time from ionophoretic application of 5-HT, suggesting that inhibition of NMDA-evoked activity by BTS 54 505 was not mediated by 5-HT uptake blockade. 6 These results suggest that BTS 54 505 inhibits NMDA-evoked activity, and the observation that this effect is unlikely to be due to raised levels of endogenous 5-HT following monoamine uptake blockade indicate that BTS 54 505 may interact directly with the NMDA receptor ionophore complex.

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Effect on radiolabelled-monoamine uptake in vitro of plasma taken from healthy volunteers administered the antidepressant sibutramine HCl

et al. 1990

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Sibutramine HCl, a monoamine reuptake inhibitor type of antidepressant, was administered to healthy male volunteers as either a single dose (12.5 or 50 mg) or repeated treatment (5-20 mg once daily or 15 mg twice daily). Plasma, obtained at regular intervals during and after sibutramine HCl or placebo treatment, was assayed in vitro for its ability to inhibit the uptake of [3H]-noradrenaline (NA) by rat cortical synaptosomes, [3H]-5-hydroxytryptamine (5HT) by human platelets and [14C]-dopamine (DA) by rat striatal synaptosomes. After both single and repeated sibutramine HCl administration, the rank order of uptake inhibition was [3H]-NA greater than [3H]-5HT greater than [14C]-DA. The level of monoamine uptake inhibition increased on daily administration to a plateau 4-6 days after initiation of treatment, for example, approximately 60% and 40% inhibition of [3H]-NA and [3H]-5HT, respectively, following 15 mg sibutramine HCl twice daily. The pattern of monoamine uptake inhibition following sibutramine HCl administration to man is similar to that observed in sibutramine HCl-treated rats, and probably at least partly reflects inhibition of uptake by drug metabolites in both species. The inhibition of monoamine uptake following sibutramine HCl administration to man is consistent with an antidepressant effect.

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BTS 54 524—an Approach to a Rapidly Acting Antidepressant

Cited by 5 publications

References 4 publications

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

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

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

Effect on radiolabelled-monoamine uptake in vitro of plasma taken from healthy volunteers administered the antidepressant sibutramine HCl

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