Efficacy of antipsychotic agents at human 5-HT1A receptors determined by [3H]WAY100,635 binding affinity ratios:: Relationship to efficacy for G-protein activation

5-HT1A receptors are implicated in the aetiology of schizophrenia. Herein, the influence of 15 antipsychotics on the binding of the selective 'neutral' antagonist, [H-3]WAY100,635 ([H-3]N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)-cyclo-hexanecarboxamide), was examined at human 5-HT1A receptors expressed in Chinese Hamster Ovary cells. In competition binding experiments, 5-HT displayed biphasic isotherms which were shifted to the right in the presence of the G-protein uncoupling agent, GTP gammaS (100 muM). In analogy, the isotherms of ziprasidone, quetiapine and S16924 (((R-2-{1-[2-(2,3-dihydro-benzo[1,4]dioxin-5-yloxy)-ethyl]-pyrrolidin-3yl}-1-(4-fluoro-phenyl)-ethanone), were displaced to the right by GTP gammaS, consistent with agonist actions. Binding of several other antipsychotics, such as ocaperidone, olanzapine and risperidone, was little influenced by GTP gammaS. Isotherms of the neuroleptics, haloperidol, chlorpromazine and thioridazine were shifted to the left in the presence of GTP gammaS, suggesting inverse agonist properties. For most ligands, the magnitude of affinity changes induced by GTP gammaS (alteration in pK(i) values) correlated well with their previously determined efficacies in [S-35]GTP gammaS binding studies [Eur. J. Pharmacol. 355 (1998) 245]. In contrast, the affinity of the 'atypical' antipsychotic agent, clozapine, which is a known partial agonist at 5-HT1A receptors, was less influenced by GTP gammaS. When the ratio of high-/low affinity values was plotted against efficacy, hyperbolic isotherms were obtained, consistent with a modified ternary complex model which assumes that receptors can adopt active conformations in the absence of agonist. In conclusion, modulation of [H-3]-WAY100,635 binding by GTP gammaS differentiated agonist vs. inverse agonist properties of antipsychotics at 5-HT1A receptors. These may contribute to differing profiles of antipsychotic activity. (C) 2001 Elsevier Science B.V. All rights reserved.