IN-VIVO OCCUPATION OF DOPAMINE D-1, D-2 AND SEROTONIN(2A) RECEPTORS BY NOVEL ANTIPSYCHOTIC DRUG, SM-9018 AND ITS METABOLITE, IN RAT-BRAIN

In vivo occupation of dopamine D-1, D-2 and serotonin (5-MT)(2A) recep tors by a novel antipsychotic drug, SM-9018 (perospirone hydrochloride -1-piperazinyl]butyl]cyclohexane-1,2-dicarboximide monohydrochloride) and its major metabolite (ID-15036; isothiazol-3-yl)-1-piperazinyl]bu tyl]-1-hydroxy-1, 2-cyclohexanedicarboximide) was measured in rat brai n using N-ethoxycarbonyl-2-ethoxy-1 ,2-dihydroquinoline (EEDQ), an irr eversible antagonist, at these receptor sites. SM-9018 and its metabol ite, ID-15036, dose-dependently reversed EEDQ-induced 5-MT2A and D-2 r eceptor inactivation, but not D-1 receptor inactivation. At lower dose s (0.1 mg/kg i.p.), SM-9018 showed a preferential occupation of the 5- MT2A receptors, with only a small effect on the D-2 receptors; while a t higher doses (1.0 and 5.0 mg/kg i.p.): it was nearly equipotent in i ts occupation of both the D-2 (77.8%) and the 5-HT2A receptors (78.6%) . On the other hand, ID-15036 was more potent in occupying the 5-MT2A than the D-2 receptors even at higher doses (1.0 and 5.0 mg/kg i.p.). We previously reported that atypical antipsychotic drugs, such as cloz apine, were characterized by a high occupancy of the 5-MT2A receptors, with a low or minimum occupancy of the D-2 receptors in vivo. The pre sent study suggests that SM-9018 and its metabolite ID-15036 show a pr eferential tendency to occupy 5-MT2A receptors, and that the clozapine -like atypical properties of SM-9018 may be due to some pharmacologica l action of both the SM-9018 itself and its metabolite, ID-15063.