Potent antagonism of 5-HT3 and 5-HT6 receptors by olanzapine

The interaction of the psychotropic agent olanzapine with serotonin 5-HT3 a nd 5-HT6 receptors was investigated. Olanzapine did not contract the isolat ed guinea pig ileum, but blocked contractions induced by the 5-HT3 receptor agonist 2-methyl serotonin (2-CH3 5-HT) with a pK(B) value of 6.38 +/- 0.0 3, close to the affinity of the 5-HT3 receptor antagonist ondansetron. The atypical antipsychotic risperidone (1 muM) did not significantly inhibit 2- CH3 5-HT-induced contractions. Olanzapine had high affinity (pK(i) = 8.30 /- 00.06) for human 5-HT6 receptors in radioligand binding studies. Olanzap ine did not stimulate [S-35]guanosine-5'-O-(3-thio)triphosphate ([S-35]GTP gammaS) binding to the G protein G, in cells containing human 5-HT6 recepto rs, but inhibited 5-HT-stimulated [S-35]GTP gammaS binding (pK(B) = 7.38 +/ - 0.16). Among other antipsychotics investigated, clozapine antagonized 5-H T6 receptors with a pK(B) = 7.42 +/- 0.15, ziprasidone was three-fold less potent, and risperidone, quetiapine and haloperidol were weak antagonists. Thus, olanzapine was not an agonist, but was a potent antagonist at 5-HT6 r eceptors and had marked antagonism at 5-HT3 receptors. (C) 2001 Elsevier Sc ience B.V. All rights reserved.