POTENT, SELECTIVE TETRAHYDRO-BETA-CARBOLINE ANTAGONISTS OF THE SEROTONIN 2B (5HT(2B)) CONTRACTILE RECEPTOR IN THE RAT STOMACH FUNDUS

A series of potent, selective 5HT(2B) receptor antagonists has been id entified based upon yohimbine, with SAR studies resulting in a 1000-fo ld increase in 5HT(2B) receptor affinity relative to the starting stru cture (-log K(B)s > 10.0 have been obtained). These high-affinity tetr ahydro-beta-carboline antagonists are able to discriminate among the 5 HT(2) family of serotonin receptors, with members of the series showin g selectivities of more than 100-fold versus both the 5HT(2A) and 5HT( 2C) receptors based upon radioligand binding and functional assays. As the first compounds reported with such selectivity and enhanced recep tor affinity, these tetrahydro-beta-carboline antagonists are useful t ools for elucidating the role of serotonin acting at the 5HT(2B) recep tor in normal and disease physiology.