5-HT3- and 5-HT2C-antagonist properties of cyamemazine: significance for its clinical anxiolytic activity

Rationale: Cyamemazine is a neuroleptic compound which possesses anxiolytic properties in humans, On the other hand, 5-HT3- and 5-HT2C-receptors have been implicated in anxiety disorders and a previous binding study has shown that cyamemazine possesses high affinity for both serotonin receptor types . Objective The present study was undertaken to establish whether cyamemazi ne antagonizes 5-HT3- and/or 5-HT2C-mediated responses, and whether it comp ares with reference compounds. Methods: Cyamemazine was tested for its abil ity to antagonize: (i) 5-HT3-dependent contraction of the isolated guinea-p ig ileum and bradycardic responses in the rat and (ii) 5-HT2C-dependent pho spholipase C (PLC) stimulation in rat brain membranes, Results: In isolated guinea-pig ileum, cyamemazine potently and competitively antagonized 5-HT- dependent contractions (pA(2)=7.52+/-0.08; n=5). In this test, cyamemazine was 5-7 times more potent (pIC(50)=6.75+/-0.13) than tropisetron (pIC(50)=6 .02+/-0.04). In rats, cyamemazine i.v. antagonized 5-HT-dependent bradycard ic responses with ID50%=3.2+/-1.5 mg/kg (n=4). Finally, in rat brain membra nes cyamemazine antagonized 5-HT2C-dependent PLC stimulation with K-i=424 n M (mianserin exhibits a K-i=113 nM). Conclusions: Cyamemazine behaves as an antagonist at both 5-HT3- and 5-HT2C-receptors, which compares well with r eference compounds. These 5-HT3 and 5-HT2C-antagonistic actions of cyamemaz ine can be involved, at least in part, in its beneficial therapeutic action s in anxiety disorders.