Cyclic benzamides as mixed dopamine D2/serotonin 5-HT2 receptor antagonists: potential atypical antipsychotic agents.
A series of novel 4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl) cyclic amides was prepared and evaluated as potential antipsychotic agents. The target compounds were examined in vitro for their binding affinities to the dopamine D2, serotonin 5-HT2, and serotonin 5-HT1a receptors and in vivo for their ability to antagonize the apomorphine-induced climbing response in mice. Derivatives that exhibited good D2/5-HT2 selectivity in vitro and good potency in vivo were selected for further evaluation in tests designed to assess their potential extrapyramidal side effect liability. Structural modifications discussed herein focus on the bicyclic amide subunit leading to the preparation of a variety of heterocyclic ring systems (i.e., phthalimide, isoindolinone, isoquinolinone, benzazepinone, indazolone, phthalazinone, 4-methyl phthalazinone, benzisothiazolone 1,1-dioxide, benzotriazinone, homophthalimide, benzisothiazolone, phthalazinedione, quinazoline, and saturated phthalazinones). The potency and selectivity within this series was found to be dependent on ring size, nature of the covalent linking unit, relative position of the functional groups, degree of unsaturation, and relative stereochemistry. In general, the cyclic benzamides examined in this investigation exhibited receptor binding activities indicative of potential atypical antipsychotic agents. Several of these derivatives possessed in vivo activities that suggest they would be useful in the treatment of schizophrenia and would have a low propensity to induce extrapyramidal side effects. Two potent analogues were identified and selected for further evaluation: 2-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-1-isoind olinone (31) and (+-)-cis-2-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-butyl)- 4a,5,6,7,8,8a-hexahydro-1(2H)-phthalazinone hydrochloride (52).
Norman
M H
MH
Division of Organic Chemistry, Burroughs Wellcome Company, Research Triangle Park, North Carolina 27709.
Rigdon
G C
GC
Navas
F
F
Cooper
B R
BR
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001667:Binding, Competitive; D002375:Catalepsy / Q000139:chemically induced; D003342:Corpus Striatum / Q000378:metabolism; D003500:Cyclization; D065127:Dopamine D2 Receptor Antagonists; D005625:Frontal Lobe / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D007211:Indoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D054833:Isoindoles; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D010793:Phthalazines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology
D014150:Antipsychotic Agents; D065127:Dopamine D2 Receptor Antagonists; D007211:Indoles; D054833:Isoindoles; D010793:Phthalazines; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013844:Thiazoles; C088805:2-(4-(4-(1,2-benzisothiazol-3-yl)piperazin-1-yl)butyl)-1-isoindolinone; C088806:2-(4-(4-(3-(1,2-benzisothiazolyl))-1-piperazinyl)butyl)-4a,5,6,7,8,8a-hexahydro-1(2H)-phthalazinone; D001058:Apomorphine