Audia J E, Evrard D A, Murdoch G R, Droste J J, Nissen J S, Schenck K W, Fludzinski P, Lucaites V L, Nelson D L, Cohen M L
Lilly Research Laboratories, Division of Eli Lilly & Company, Indianapolis, Indiana 46285, USA.
J Med Chem. 1996 Jul 5;39(14):2773-80. doi: 10.1021/jm960062t.
A series of potent, selective 5HT2B receptor antagonists has been identified based upon yohimbine, with SAR studies resulting in a 1000-fold increase in 5HT2B receptor affinity relative to the starting structure (-log KBS > 10.0 have been obtained). These high-affinity tetrahydro-beta-carboline antagonists are able to discriminate among the 5HT2 family of serotonin receptors, with members of the series showing selectivities of more than 100-fold versus both the 5HT2A and 5HT2C receptors based upon radioligand binding and functional assays. As the first compounds reported with such selectivity and enhanced receptor affinity, these tetrahydro-beta-carboline antagonists are useful tools for elucidating the role of serotonin acting at the 5HT2B receptor in normal and disease physiology.
基于育亨宾已鉴定出一系列强效、选择性5HT2B受体拮抗剂，通过构效关系研究，相对于起始结构，5HT2B受体亲和力提高了1000倍（已获得-log KBS>10.0）。这些高亲和力的四氢-β-咔啉拮抗剂能够区分5HT2家族的血清素受体，基于放射性配体结合和功能测定，该系列成员对5HT2A和5HT2C受体的选择性均超过100倍。作为首次报道的具有这种选择性和增强受体亲和力的化合物，这些四氢-β-咔啉拮抗剂是阐明血清素在正常和疾病生理学中作用于5HT2B受体的有用工具。
