Potent, selective tetrahydro-beta-carboline antagonists of the serotonin 2B (5HT2B) contractile receptor in the rat stomach fundus

  • J Med Chem. 1996 Jul 5;39(14):2773-80. doi: 10.1021/jm960062t.
J E Audia  1 ,  D A Evrard ,  G R Murdoch ,  J J Droste ,  J S Nissen ,  K W Schenck ,  P Fludzinski ,  V L Lucaites ,  D L Nelson ,  M L Cohen
Affiliations
  • 1. Lilly Research Laboratories, Division of Eli Lilly & Company, Indianapolis, Indiana 46285, USA.
PMID: 8709108 DOI: 10.1021/jm960062t
Abstract

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.

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