Nitrogen-containing heteroalicycles with serotonin 5-HT3 and 5-HT4 receptor binding affinities -: Development of gastroprokinetic and antiemetic agents

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 D-2 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.