Muscarinic mechanisms of antipsychotic atypicality.
The interactions of the atypical antipsychotic drugs (APD) clozapine, olanzapine, risperidone, quetiapine and ziprasidone with muscarinic receptors were reviewed. Only clozapine and olanzapine have marked affinity for muscarinic receptors in radioligand binding studies; however, the affinity of these compounds is considerably lower than classical muscarinic antagonists. Although functional assays in cell lines transfected with muscarinic receptors suggest that olanzapine and clozapine have weak partial agonist activity at muscarinic receptors, particularly M4 receptors, studies in vitro and in vivo indicate that the compounds function as antagonists. In animal studies and in humans, clozapine has pronounced antimuscarinic effects whereas olanzapine has weak antimuscarinic effects. However, olanzapine significantly occupies central muscarinic receptors in humans. Overall, the role of muscarinic receptors in the antipsychotic effects of clozapine and olanzapine is controversial and complex.
Bymaster
Frank P
FP
Neuroscience Research Division, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285-0510, USA. F.Bymaster@lilly.com
Felder
Christian C
CC
Tzavara
Eleni
E
Nomikos
George G
GG
Calligaro
David O
DO
Mckinzie
David L
DL
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D001519:Behavior / Q000187:drug effects; D001667:Binding, Competitive; D018678:Cholinergic Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D007700:Kinetics; D023421:Models, Animal; D009433:Neural Inhibition / Q000187:drug effects; D011618:Psychotic Disorders / Q000188:drug therapy*; D011976:Receptors, Muscarinic / Q000145:classification / Q000187:drug effects / Q000378:metabolism*; D015290:Second Messenger Systems / Q000187:drug effects
D014150:Antipsychotic Agents; D018678:Cholinergic Agents; D011976:Receptors, Muscarinic; D000109:Acetylcholine