Succinimide derivatives. II. Synthesis and antipsychotic activity of N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-1,2-cis- cyclohexanedicarboximide (SM-9018) and related compounds.
Cyclic imides bearing omega-(4-benzisothiazol-3-yl-1-piperazinyl)alkyl moieties were synthesized and tested for antipsychotic activity. The in vitro binding affinities of these compounds were examined for dopamine 2 (D2) and serotonin 2 (5-HT2) receptor sites. Structure-activity relationships within these series are discussed. One of these compounds, N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-1,2-cis- cyclohexamedicarboximide (SM-9018), was found to be more potent and more selective in vivo than tiospirone in its antipsychotic activity. SM-9018 (17) is currently undergoing clinical evaluation as a selective antipsychotic agent.
Ishizumi
K
K
Sumitomo Pharmaceuticals Research Center, Osaka, Japan.
Kojima
A
A
Antoku
F
F
Saji
I
I
Yoshigi
M
M
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced / Q000523:psychology; D002492:Central Nervous System Depressants / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D006220:Haloperidol / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D054833:Isoindoles; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D011619:Psychotropic Drugs / Q000494:pharmacology; D051381:Rats; D012702:Serotonin Antagonists / Q000494:pharmacology; D013141:Spiro Compounds / Q000494:pharmacology; D013239:Stereotyped Behavior / Q000187:drug effects; D013329:Structure-Activity Relationship; D013388:Succinimides / Q000138:chemical synthesis* / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology*
D014150:Antipsychotic Agents; D002492:Central Nervous System Depressants; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D007211:Indoles; D054833:Isoindoles; D011619:Psychotropic Drugs; D012702:Serotonin Antagonists; D013141:Spiro Compounds; D013388:Succinimides; D013844:Thiazoles; C042709:tiospirone; D006220:Haloperidol; C065533:perospirone