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

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 IP3 in cell lines transfected with 5-HT2A or 5-HT2B receptors with IC50 values of 30-40 nM. Olanzapine weakly blocked 5-HT-induced formation of IP3 in cell lines transfected with 5-HT2C receptors, but in this cell line potently inhibited 5-HT-stimulated [S-35]GTP gamma 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 [S-35]GTP gamma S binding assays. However, olanzapine antagonized agonist-induced effects in muscarinic Mg cells with a Ki value of 350 nM. In isolated tissue studies, olanzapine potently blocked agonist-induced effects at alpha(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-HT2A, 5-HT2B, 5-HT2C, alpha(1)-adrenergic and histamine H-1 receptors. Olanzapine was a weaker antagonist at muscarinic and dopamine D1 receptors. (C) 1999 Elsevier Science B.V. AU rights reserved.