5-HT₃- and 5-HT_2C-antagonist properties of cyamemazine: significance for its clinical anxiolytic activity

Abstract 

Rationale: Cyamemazine is a neuroleptic compound which possesses anxiolytic properties in humans. On the other hand, 5-HT₃- and 5-HT_2C-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 cyamemazine antagonizes 5-HT₃- and/or 5-HT_2C-mediated responses, and whether it compares with reference compounds. Methods: Cyamemazine was tested for its ability to antagonize: (i) 5-HT₃-dependent contraction of the isolated guinea-pig ileum and bradycardic responses in the rat and (ii) 5-HT_2C-dependent phospholipase C (PLC) stimulation in rat brain membranes. Results: In isolated guinea-pig ileum, cyamemazine potently and competitively antagonized 5-HT-dependent contractions (pA₂=7.52±0.08; n=5). In this test, cyamemazine was 5–7 times more potent (pIC₅₀=6.75±0.13) than tropisetron (pIC₅₀=6.02±0.04). In rats, cyamemazine i.v. antagonized 5-HT-dependent bradycardic responses with ID_50%=3.2±1.5 mg/kg (n=4). Finally, in rat brain membranes cyamemazine antagonized 5-HT_2C-dependent PLC stimulation with K_i=424 nM (mianserin exhibits a K_i=113 nM). Conclusions: Cyamemazine behaves as an antagonist at both 5-HT₃- and 5-HT_2C-receptors, which compares well with reference compounds. These 5-HT₃- and 5-HT_2C-antagonistic actions of cyamemazine can be involved, at least in part, in its beneficial therapeutic actions in anxiety disorders.