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Neuronal SignalingMembrane Transporter/Ion Channel-
Sibutramine hydrochloride monohydrate ??????????????????5-HT(serotonin) ??????????????????????????????????????? (SNRI)???Sibutramine ?????????????????? K+??????KV4.3???IC50??? 17.3 ??M???
Serotonin TransporterPotassium Channel
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生物活性
Description
Sibutramine hydrochloride monohydrate is a novel5-HT(serotonin) and noradrenaline reuptake inhibitor (SNRI). TheIC50for Sibutramine block of voltage-gated K+channel (KV)4.3is 17.3 ??M.
IC50& Target
5-HT (serotonin) reuptake[1]
IC50: 17.3 ??M (KV4.3)[2]
In Vitro
Sibutramine is a novel 5-HT (serotonin) and noradrenaline reuptake inhibitor (SNRI). Sibutramine reduces the food intake of rodents and this effect is partially or completely reversed by pretreating with 5-HT or noradrenaline antagonists, indicating that both neurotransmitters are involved in sibutramine's hypophagic effect[1]. Sibutramine causes the concentration-dependent block of the KV1.3 and KV3.1 currents with IC50s of 3.7 and 32.7 ??M, respectively. The steady-state currents of KV1.3 and KV3.1 are decreased by Sibutramine in a concentration-dependent manner with IC50s of 3.7??0.7 (n=6) and 32.7??5.0 ??M (n=5), respectively[2].
In Vivo
Sibutramine (SIB) (5 mg/kg ip), which blocks the reuptake of both 5-hydroxytryptamine (5-HT) and noradrenaline (NA), also requires ARC pro-opiomelanocortin (POMC) neurons to achieve its appetitive effects in male and female mice. Sibutramine (5 mg/kg) suppresses 3-hour dark cycle food intake to a comparable extent in young adult and middle-aged male and female POMC-EGFP mice[3]. In normal Wistar rats, 3 mg/kg Sibutramine produces a marked (~30%) inhibition of food intake on the first day of dosing. Consistent with published data, the effects of Sibutramine on food intake diminished with time, although cumulative food intake over the 9-day study is significantly (P<0.001) lower in Sibutramine-treated (213.3??5.7 g) than in vehicle-treated (260.2??3.0 g) rats. Sibutramine also significantly reduces overall body weight gain (vehicle 30??2 g, Sibutramine 14??3 g; P<0.001)[4].
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References
[1].Heal DJ, et al. Sibutramine: a novel anti-obesity drug. A review of the pharmacological evidence to differentiate it from d-amphetamine and d-fenfluramine. Int J Obes Relat Metab Disord. 1998 Aug;22 Suppl 1:S18-28; discussion S29.
[2].Kim SE, et al. Open channel block of A-type, kv4.3, and delayed rectifier K+channels, KV1.3 and KV3.1, bySibutramine. J Pharmacol Exp Ther. 2007 May;321(2):753-62.
[3].Burke LK, et al. 5-HT obesity medication efficacy via POMC activation is maintained during aging. Endocrinology. 2014 Oct;155(10):3732-8.
[4].Turnbull AV, et al. Selective antagonism of the NPY Y5 receptor does not have a major effect on feeding in rats. Diabetes. 2002 Aug;51(8):2441-9.