Antagonism by olanzapine of dopamine D1, serotonin2, muscarinic, histamine H1 and α1-adrenergic receptors in vitro

Abstract The atypical antipsychotic olanzapine has relatively high affinity for a number of neuronal receptors in radioreceptor binding assays. The ability of olanzapine to activate or antagonize a number of neuronal receptors was investigated in vitro, in cell lines transfected selectively with receptor subtypes and in receptor-selective isolated tissue studies. Olanzapine had no agonist activity at any of the receptors examined. However, olanzapine was a potent antagonist of 5-HT-stimulated increases in IP 3 in cell lines transfected with 5-HT 2A or 5-HT 2B receptors with IC 50 values of 30–40 nM. Olanzapine weakly blocked 5-HT-induced formation of IP 3 in cell lines transfected with 5-HT 2C receptors, but in this cell line potently inhibited 5-HT-stimulated [ 35 S ]GTP γ S binding with a K i value of 15 nM. Olanzapine blocked dopamine-stimulated adenylyl cyclase in rat retina with modest potency ( K i =69 nM), consistent with its relatively low affinity for dopamine D1 receptors. Olanzapine blocked agonist-induced activities at the muscarinic receptor subtypes M 1 , M 2 , M 3 , and M 5 with K i values of 70, 622, 126, and 82 nM, respectively. In studies using cell lines transfected with muscarinic M 4 receptors, olanzapine and the atypical antipsychotic clozapine did not have agonist activities as determined with cAMP inhibition and stimulation assays, arachidonic acid release and [ 35 S ]GTP γ S binding assays. However, olanzapine antagonized agonist-induced effects in muscarinic M 4 cells with a K i value of 350 nM. In isolated tissue studies, olanzapine potently blocked agonist-induced effects at α 1 -adrenergic and histamine H 1 receptors ( K B =9 and 19 nM, respectively). Thus, olanzapine was an antagonist at all receptors investigated and was a particularly potent antagonist at 5-HT 2A , 5-HT 2B , 5-HT 2C , α 1 -adrenergic and histamine H 1 receptors. Olanzapine was a weaker antagonist at muscarinic and dopamine D1 receptors.