title: In vivo occupation of dopamine D1, D2 and serotonin2A receptors by novel antipsychotic drug, SM-9018 and its metabolite, in rat brain.
abstract: In vivo occupation of dopamine D1, D2 and serotonin (5-HT)2A receptors by a novel antipsychotic drug, SM-9018 (perospirone hydrochloride; cis-N- [4- [4- (1,2-benzisothiazol-3-yl)- 1-piperazinyl]butyl]cyclohexane-1,2-dicarboximide monohydrochloride) and its major metabolite (ID-15036; N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-1-hydroxy-1 , 2-cyclohexanedicarboximide) was measured in rat brain using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an irreversible antagonist, at these receptor sites. SM-9018 and its metabolite, ID-15036, dose-dependently reversed EEDQ-induced 5-HT2A and D2 receptor inactivation, but not D1 receptor inactivation. At lower doses (0.1 mg/kg i.p.), SM-9018 showed a preferential occupation of the 5-HT2A receptors, with only a small effect on the D2 receptors; while at higher doses (1.0 and 5.0 mg/kg i.p.), it was nearly equipotent in its occupation of both the D2 (77.8%) and the 5-HT2A receptors (78.6%). On the other hand, ID-15036 was more potent in occupying the 5-HT2A than the D2 receptors even at higher doses (1.0 and 5.0 mg/kg i.p.). We previously reported that atypical antipsychotic drugs, such as clozapine, were characterized by a high occupancy of the 5-HT2A receptors, with a low or minimum occupancy of the D2 receptors in vivo. The present study suggests that SM-9018 and its metabolite ID-15036 show a preferential tendency to occupy 5-HT2A receptors, and that the clozapine-like atypical properties of SM-9018 may be due to some pharmacological action of both the SM-9018 itself and its metabolite, ID-15063.
authors.affiliation: Department of Psychiatry, Hokkaido University School of Medicine, Sapporo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Takahashi
authors.forename: I
authors.initials: I
authors.lastname: Kusumi
authors.forename: T
authors.initials: T
authors.lastname: Ishikane
authors.forename: T
authors.initials: T
authors.lastname: Koyama
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000493:pharmacokinetics*; D001667:Binding, Competitive / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects*; D018492:Dopamine Antagonists; D007211:Indoles / Q000493:pharmacokinetics*; D054833:Isoindoles; D008297:Male; D011804:Quinolines; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D013844:Thiazoles / Q000493:pharmacokinetics*
chemical_list: D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D007211:Indoles; D054833:Isoindoles; D011804:Quinolines; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D013844:Thiazoles; C000470:EEDQ; C065533:perospirone