5-HT3- and 5-HT2C-antagonist properties of cyamemazine: significance for its clinical anxiolytic activity.
BACKGROUND
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 cyamemazine antagonizes 5-HT3- and/or 5-HT2C-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-HT2C-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 ID50% = 3.2 +/- 1.5 mg/kg (n = 4). Finally, in rat brain membranes cyamemazine antagonized 5-HT2C-dependent PLC stimulation with Ki = 424 nM (mianserin exhibits a Ki = 113 nM).


CONCLUSIONS
Cyamemazine behaves as an antagonist at both 5-HT3- and 5-HT2C-receptors, which compares well with reference compounds. These 5-HT3- and 5-HT2C-antagonistic actions of cyamemazine can be involved, at least in part, in its beneficial therapeutic actions in anxiety disorders.
Alvarez-Guerra
M
M
INSERM U400, Faculté de Médecine de Créteil & Rhône-Poulenc-Rorer, Montrouge, France.
d'Alché-Birée
F
F
Wolf
W A
WA
Vargas
F
F
Dib
M
M
Garay
R P
RP
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002421:Caudate Nucleus / Q000201:enzymology; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008566:Membranes / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010640:Phenothiazines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000187:drug effects*; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000378:metabolism
D014151:Anti-Anxiety Agents; D014150:Antipsychotic Agents; D010640:Phenothiazines; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; C028457:cyamemazine; D010738:Type C Phospholipases