Clozapine is a potent and selective muscarinic M4 receptor agonist.
Clozapine was studied in functional assays at human muscarinic M1-M5 receptors expressed in Chinese hamster ovary cells. Clozapine was a full agonist at the muscarinic M4 receptor (EC50 = 11 nM), producing inhibition of forskolin-stimulated cAMP accumulation. In contrast, clozapine potently antagonized agonist-induced responses at the other four muscarinic receptor subtypes. Selective stimulation of M4 receptors may, in part, explain the hypersalivation observed clinically with clozapine. Moreover, the unique overall muscarinic profile of clozapine may contribute to its atypical antipsychotic efficacy.
Zorn
S H
SH
Pfizer Inc., Department of Neuroscience, Groton, CT 06340.
Jones
S B
SB
Ward
K M
KM
Liston
D R
DR
D000818:Animals; D016466:CHO Cells; D002217:Carbachol / Q000494:pharmacology; D003024:Clozapine / Q000378:metabolism / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D018721:Muscarinic Agonists; D019832:N-Methylscopolamine; D010276:Parasympatholytics / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism; D012472:Salivation / Q000187:drug effects; D012602:Scopolamine Derivatives / Q000494:pharmacology
D018721:Muscarinic Agonists; D010276:Parasympatholytics; D010716:Phosphatidylinositols; D012602:Scopolamine Derivatives; D005576:Colforsin; D002217:Carbachol; D000242:Cyclic AMP; D003024:Clozapine; D019832:N-Methylscopolamine