We determined the affinities of clozapine and 21 other typical and atypical antipsychotic agents for the cloned 5-hydroxytryptamine-I C (5-HT1) receptor. For these studies, 5-HT1 receptors were transiently expressed in COS-7 cells using the vector pSVK3-5HT1c. We discovered that clozapine and several other putative typical and atypical antipsychotic agents (loxapine> tiosperone> SCH23390> fiuperlapine> nlapine> chlorprom-azine) had relatively high affinities(7-30 nM) for the cloned 5-HT1 receptor. Other antipsychotic agents (nsperidone> tenilapme> mesondazine> thiondazine> cis-fluphenthixol) had inter-mediate affinities (30.-i 00 nM), whereas many other antipsy-chotics (fluphenazine> spiperone> amperozide> melperone> thiothixene> halopendol, metoclopramide, pimozide, domperidone, sulpuride) had low affinities(> 500 nM) for the cloned 5-HT1 receptor. The results indicate that although several putative atypical antipsychotic agents have high affinities for the cloned rat 5-HT1 receptor, the spectrum of drug binding does not correlate with the atypical nature of these compounds.

Clozapine is an atypical antipsychotic agent which appears to have special efficacy for treatment-resistant schizophrenia (Claghorn et aL, 1987; Kane et a!., 1988; Meltzer, 1989). Al-though the exact mechanism of action of clozapine remains unknown, recent studies have suggested that a major predictor of the atypical properties of clozapine and other antipsychotics is a functional interaction with 5-HT2 receptors(Meltzer et a!., 1989; Seeman, 1990; Niemegeers et at., 1990). In addition to the 5-HT2 receptor, clozapine also binds with high affinity to muscarinic(Miller and Hiley, 1974), alpha-i adrenergic(Cohen and Lipinski, 1986) and dopamine D1 (Altar et a!., 1988) recep-tors. Recently, Canton et aL (1990) suggested that 5-HT1 binding might also be important for the unique actions of clozapine.