Delagrange P, Emerit M B, Merahi N, Abraham C, Morain P, Rault S, Renard P, Pfeiffer B, Guardiola-Lemaître B, Hamon M
IRIS, Courbevoie, France.
Eur J Pharmacol. 1996 Dec 5;316(2-3):195-203. doi: 10.1016/s0014-2999(96)00680-2.
The interaction of S 21007 [5-(4-benzyl piperazin-1-yl)4H pyrrolo [1,2-a]thieno[3,2-e]pyrazine] with serotonin 5-HT3 receptors was investigated using biochemical, electrophysiological and functional assays. Binding studies using membranes from N1E-115 neuroblastoma cells showed that S 21007 is a selective high affinity (IC50 = 2.8 nM) 5-HT3 receptor ligand. As expected of an agonist, S 21007 stimulated the uptake of [14C]guanidinium (EC50 approximately 10 nM) in NG 108-15 cells exposed to substance P, and this effect could be prevented by the potent 5-HT3 receptor antagonist ondansetron. In addition, like 5-HT and other 5-HT3 receptor agonists (phenylbiguanide and 3-chloro-phenylbiguanide), S 21007 (EC50 = 27 microM) produced a rapid inward current in N1E-115 cells. The 5-HT3 receptor agonist action of S 21007 was also demonstrated in urethane-anaesthetized rats as this drug (120 micrograms/kg i.v.) triggered the Bezold-Jarisch reflex (rapid fall in heart rate), and this action could be prevented by pretreatment with the potent 5-HT3 receptor antagonist zacopride. Finally, in line with its 5-HT3 receptor agonist properties, S 21007 also triggered emesis in the ferret. Evidence for 5-HT3 receptor antagonist-like properties of S 21007 was also obtained in some of these experiments since previous exposure to this compound prevented both the 5-HT-induced current in N1E-115 cells and the Bezold-Jarisch reflex elicited by an i.v. bolus of 5-HT (30 micrograms/kg) in urethane-anaesthetized rats. These data suggest that S 21007 is a selective 5-HT3 receptor agonist which can exhibit antagonist-like properties either by triggering a long lasting receptor desensitization or by a partial agonist activity at 5-HT3 receptors in some tissues.
运用生化、电生理和功能分析方法，研究了S 21007 [5-(4-苄基哌嗪-1-基)-4H-吡咯并[1,2-a]噻吩并[3,2-e]吡嗪]与5-羟色胺5-HT3受体的相互作用。使用N1E-115神经母细胞瘤细胞膜进行的结合研究表明，S 21007是一种选择性高亲和力（IC50 = 2.8 nM）的5-HT3受体配体。正如激动剂所预期的那样，S 21007刺激了暴露于P物质的NG 108-15细胞中[14C]胍的摄取（EC50约为10 nM），并且强效5-HT3受体拮抗剂昂丹司琼可阻止这种效应。此外，与5-羟色胺和其他5-HT3受体激动剂（苯基双胍和3-氯苯基双胍）一样，S 21007（EC50 = 27 microM）在N1E-115细胞中产生了快速内向电流。S 21007的5-HT3受体激动剂作用在乌拉坦麻醉的大鼠中也得到了证实，因为这种药物（120微克/千克静脉注射）引发了贝佐尔德-雅里什反射（心率迅速下降），并且强效5-HT3受体拮抗剂扎考必利预处理可阻止这种作用。最后，与其5-HT3受体激动剂特性一致，S 21007在雪貂中也引发了呕吐。在其中一些实验中还获得了S 21007具有5-HT3受体拮抗剂样特性的证据，因为先前接触这种化合物可阻止N1E-115细胞中5-羟色胺诱导的电流以及乌拉坦麻醉大鼠静脉注射5-羟色胺（30微克/千克）推注引发的贝佐尔德-雅里什反射。这些数据表明，S 21007是一种选择性5-HT3受体激动剂，它可以通过触发持久的受体脱敏或通过在某些组织的5-HT3受体上的部分激动剂活性而表现出拮抗剂样特性。
