Novel selective and partial agonists of 5-HT3 receptors. Part 1. Synthesis and biological evaluation of piperazinopyrrolothienopyrazines.
Novel selective and partial agonists of 5-HT3 receptors. Part 1. Synthesis and biological evaluation of piperazinopyrrolothienopyrazines.
复制标题
5-HT3 受体的新型选择性和部分激动剂。
DOI：
10.1002/chin.199635160
复制
发表时间：
1996
影响因子：
7.3
通讯作者：
M. Hamon
中科院分区：
文献类型：
--
作者：
S. Rault;J. Lancelot;H. Prunier;M. Robba;P. Renard;P. Delagrange;B. Pfeiffer;D. Caignard;B. Guardiola‐Lemaître;M. Hamon
制备了一系列哌嗪吡咯[1,2- A]噻吩[3,2-e]-和-[2,3-e]吡嗪衍生物，并对其进行了评价，以确定其对5-HT3受体具有高亲和力和对其他5-HT受体亚型具有高选择性的必要条件。系统地探讨了哌嗪和吡咯噻吩基噻吩环上的各种取代，以及哌嗪被其他环胺取代的情况。最好的化合物是在5-HT3受体的纳摩尔亲和力范围内，具有高到非常高的选择性（14b的选择性高达10,000）。这些高亲和性化合物在噻吩环上共有一个苯基或烯丙基哌嗪取代基，而在噻吩环上没有取代基。其中五种化合物（1a, 4b, 13a，b和14b）已在Von Bezold-Jarisch反射中进行了评估，并被定性为部分激动剂。其中一种，13a，在体内非常低剂量的光/暗试验中显示出有效的抗焦虑样活性。
A series of piperazinopyrrolo[1,2-a]thieno[3,2-e]- and -[2,3-e]pyrazine derivatives were prepared and evaluated in order to determine the necessary requirements for high affinity on the 5-HT3 receptors and high selectivity versus other 5-HT receptor subtypes. Various substitutions on the piperazine and the thiophene ring of the pyrrolothienopyrazine moieties were systematically explored as well as replacement of the piperazine by other cyclic amines. The best compounds are in the nanomolar range of affinity of 5-HT3 receptors with high to very high selectivity (up to 10,000 for 14b). These high-affinity compounds have in common a benzyl- or allylpiperazine substituent with no substitutions on the thiophene ring. Five of these compounds (1a, 4b, 13a,b, and 14b) have been evaluated on the Von Bezold-Jarisch reflex and were characterized as partial agonists. One of them, 13a, has shown in vivo at very low dose a potent anxiolytic-like activity in the light/dark test.