Binding of antipsychotic drugs to human brain receptors - Focus on newer generation compounds

Using radioligand binding assays and post-mortem normal human brain tissue, we obtained equilibrium dissociation constants (K(d)s) for nine new antips ychotic drugs (iloperidone, melperone, olanzapine, ORG 5222, quetiapine, ri speridone, sertindole, ziprasidone, and zotepine), one metabolite of a new drug (9-OH-risperidone), and three older antipsychotics (clozapine, haloper idol, and pimozide) at nine different receptors (alpha (1)-adrenergic, alph a (2)-adrenergic, dopamine D-2, histamine H-1, muscarinic, and serotonin 5- HT1A, 5-HT1D, 5-HT2A, and 5-HT2C receptors). Iloperidone was the most poten t drug at the two adrenergic receptors. ORG 5222 was the most potent drug a t dopamine D-2 and 5-HT2c receptors, while ziprasidone was the most potent compound at three serotonergic receptors (5-HT1A, 5-HT1D, and 5-HT2A). At t he remaining two receptors, olanzapine was the most potent drug at the hist amine H-1 receptor (K-d=0.087 nM); clozapine at the muscarinic receptor (K- d=9 nM). Certain therapeutic and adverse effects, as well as certain drug i nteractions can be predicted from a drug's potency for blocking a specific receptor. These data can provide guidelines for the clinician in the choice of antipsychotic drug. (C) 2000 Elsevier Science Inc. All rights reserved.