Pharmacological actions of SM-9018, a new neuroleptic drug with both potent 5-hydroxytryptamine2 and dopamine2 antagonistic actions.
Pharmacological studies were undertaken to clarify the profile of cis-2-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl) butyl) hexahydro-1H-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.
Hirose
A
A
Research Laboratories, Sumitomo Pharmaceuticals Co., Ltd., Osaka, Japan.
Kato
T
T
Ohno
Y
Y
Shimizu
H
H
Tanaka
H
H
Nakamura
M
M
Katsube
J
J
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced; D018492:Dopamine Antagonists; D007211:Indoles / Q000494:pharmacology*; D054833:Isoindoles; D007650:Ketanserin / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000037:antagonists & inhibitors; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000633:toxicity; D010276:Parasympatholytics; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D012702:Serotonin Antagonists; D013134:Spiperone / Q000378:metabolism; D013239:Stereotyped Behavior / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology*
D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D007211:Indoles; D054833:Isoindoles; D010276:Parasympatholytics; D012702:Serotonin Antagonists; D013844:Thiazoles; D008694:Methamphetamine; D013134:Spiperone; D007650:Ketanserin; C065533:perospirone; D009638:Norepinephrine