有機合成化学協会誌
Online ISSN : 1883-6526
Print ISSN : 0037-9980
ISSN-L : 0037-9980
セロトニン5-HT3および5-HT4受容体に親和性を有する含窒素ヘテロ環アミド化合物
消化管運動促進剤および制吐剤の開発
賀登 志朗森江 俊哉藤原 巌吉田 直之
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1998 年 56 巻 10 号 p. 851-862

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Gastrointestinal motility dysfunctions entailed in non ulcer dyspepsia, gastroparesis and reflex oesophagitis are known to be effectively treated with the gastroprokinetic agents e.g. metoclopramide and cisapride. The mechanism of gastroprokinetic action is accepted to be correlated with agonistic activity at 5-HT4 receptor. Metoclopramide and cisapride concurrently have dopamine D2 receptor antagonistic activity, which is responsible for unfavorable side effects such as extrapyramidal symptoms and central nervous system depression. To obtain gastroprokinetic agents with more potent and selective than metoclopramide, 4-amino-N- [(4-benzyl-2-morpholinyl) methyl] -5-chloro-2-methoxy-benzamide was designed and prepared. As a result of structure-activity relationship studies, mosapride was identified as a novel gastroprokinetic agent. As an extension of this project, the N- (1-benzyl-4- methylhexahydro-1, 4-diazepin-6-yl) benzamides and carboxamides were evaluated for 5-HT3 receptor antagonistic activity, and DAT-582 was selected as an optimal compound. DAT-582 was exhibited to be highly effective for the blockade of chemotherapy-induced nausea and emesis.

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