Pharmacological Actions of SM-9018, a New Neuroleptic Drug with Both Potent 5-Hydroxytryptamine₂ and Dopamine2 Antagonistic Actions

Abstract

Pharmacological studies were undertaken to clarify the profile of cis-2-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl) butyl) hexahydro-1 H-isoindole-1,3-(2H)-dione hydrochloride (SM-9018), a new neuroleptic drug. SM-9018 had very high binding affinities for both 5-hydroxytryptamine₂ (5-HT₂) and dopamine₂ (D₂) receptors, unlike many other neuroleptics. SM-9018 also strongly inhibited 5-HT₂ receptor-mediated behavior such as tryptamine-induced clonic seizure and D₂ receptor-mediated behavior such as methamphetamine-induced hyperactivity, apomorphine-induced stereotypy and climbing behavior. SM-9018 possessed only a weak cataleptogenic activity, which may be clinically related to extrapyramidal side effects, despite its potent D₂ antagonistic activity. Moreover, SM-9018 induced weak central depressant effects such as inhibition of spontaneous locomotor activity and motor coordination, as compared with classical neuroleptics (haloperidol and chlorpromazine). These results suggest that SM-9018 is a new neuroleptic drug with both potent 5-HT₂ and D₂ antagonistic activities and with low cataleptogenic and central depressant activities.