RS 127445 is an orally active, highly selective 5-HT2B receptor antagonist with a pKi of 9.5 and a selectivity for 5-HT2B that is more than 1000 times greater than that for other related receptors such as 5-HT2A and 5-HT2C[1, 2]. 5-HT2B receptors play important roles in the central and peripheral nervous systems, participating in the regulation of various physiological functions, such as cardiovascular effects and neuronal sensitization[3]. RS 127445 can inhibit dopamine neurotransmission in the nucleus accumbens[4].
In vivo, intraperitoneal injection of RS 127445 (1-30mg/kg) in mice significantly inhibited intestinal peristalsis and reduced fecal output in a dose-dependent manner[5]. RS 127445 (10mg/kg) significantly inhibited visceral hypersensitivity induced by restraint stress in experimental visceral hypersensitivity rats when administered orally, with an inhibition rate of 74%, and also reduced defecation[6].
References:
[1] Bonhaus D W, Flippin L A, Greenhouse R J, et al. RS‐127445: a selective, high affinity, orally bioavailable 5‐HT2B receptor antagonist[J]. British journal of pharmacology, 1999, 127(5): 1075-1082.
[2] Maroteaux L. Gene structure, expression, and 5-HT2B receptor signaling[M]//5-HT2B Receptors: From Molecular Biology to Clinical Applications. Cham: Springer International Publishing, 2021: 1-32.
[3] Monassier L. 5-HT2B Receptor, the Heart and Blood Vessels[M]//5-HT2B Receptors: From Molecular Biology to Clinical Applications. Cham: Springer International Publishing, 2021: 153-163.
[4] Cathala A, Devroye C, Robert É, et al. Serotonin2B receptor blockade in the rat dorsal raphe nucleus suppresses cocaine-induced hyperlocomotion through an opposite control of mesocortical and mesoaccumbens dopamine pathways[J]. Neuropharmacology, 2020, 180: 108309.
[5] Bassil A K, Taylor C M, Bolton V J N, et al. Inhibition of colonic motility and defecation by RS‐127445 suggests an involvement of the 5‐HT2B receptor in rodent large bowel physiology[J]. British journal of pharmacology, 2009, 158(1): 252-258.
[6] Ohashi‐Doi K, Himaki D, Nagao K, et al. A selective, high affinity 5‐HT2B receptor antagonist inhibits visceral hypersensitivity in rats[J]. Neurogastroenterology & Motility, 2010, 22(2): e69-e76.
RS 127445是一种具有口服活性的高选择性5-羟色胺受体2B（5-HT2B）受体拮抗剂，pKi为9.5，对5-HT2B的选择性是对5-HT2A、5-HT2C等其他相关受体的1000倍以上[1, 2]。5-HT2B受体在中枢神经系统和外周神经系统中发挥重要作用，参与调节多种生理功能，如心血管效应和神经元敏化[3]。RS 127445能够抑制伏隔核（nucleus accumbens）中的多巴胺（dopamine）神经传递[4]。
在体内，RS 127445（1-30mg/kg）通过腹腔注射处理小鼠，显著抑制了小鼠的肠蠕动，呈剂量依赖性地减少了小鼠的粪便排出量[5]。RS 127445（10mg/kg）通过口服治疗实验性内脏超敏大鼠，显著抑制了束缚应激诱发的内脏超敏反应，抑制率为74%，还减少了排便[6]。