Clozapine and N-desmethylclozapine are potent 5-HT1C receptor antagonists.
The effects of the atypical antipsychotic drug, clozapine, and its two major metabolites in man, N-desmethylclozapine and clozapine N-oxide, on 5-HT1C receptor mediated phosphoinositide hydrolysis were studied in rat choroid plexus. Clozapine and N-desmethylclozapine antagonized 5-HT-stimulated phosphoinositide hydrolysis with IC50 values of 110 and 29.4 nM, respectively. Clozapine N-oxide was less potent. None of the compounds stimulated phosphoinositide hydrolysis per se. The Ki values for [3H]mesulergine displacement in choroid plexus were in accordance with phosphoinositide hydrolysis data. In conclusion, this study demonstrates that clozapine and one of its major metabolites in man, N-desmethylclozapine, are potent 5-HT1C receptor antagonists. These properties of clozapine and N-desmethylclozapine should be considered when the atypical effects of clozapine are evaluated in vivo.
Kuoppamäki
M
M
Department of Pharmacology, University of Turku, Finland.
Syvälahti
E
E
Hietala
J
J
D000818:Animals; D002831:Choroid Plexus / Q000187:drug effects / Q000378:metabolism; D003024:Clozapine / Q000031:analogs & derivatives* / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008784:Methysergide / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D012702:Serotonin Antagonists
D010716:Phosphatidylinositols; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D012702:Serotonin Antagonists; C058272:norclozapine; D003024:Clozapine; C079149:clozapine N-oxide; D008784:Methysergide