Nitrogen-containing heteroalicycles with serotonin receptor binding affinity: development of gastroprokinetic and antiemetic agents.

Abstract

To obtain gastroprokinetic agents with more potent and selective activity than metoclopramide and cisapride, a series of N-(4-benzyl-2-morpholinylmethyl)benzamides were designed and prepared. Their synthesis and structure-activity relationships were described. As a result, mosapride was selected as a promising candidate for potent gastroprokinetic activity with selective 5-HT4 receptor agonistic activity. As an extension to this project, the novel benzamide and the carboxamide derivatives having 1-benzyl-4-methylhexahydro-1,4-diazepine ring in the amine moiety were prepared and evaluated for 5-HT3 receptor antagonistic activity. DAT-582 was identified as an antiemetic agent in cancer chemotherapy. The asymmetric synthesis of DAT-582 and the SAR studies were briefly reviewed. In further modifications of the N-(1-benzyl-4-methylhexahydro-1,4-diazepin-6-yl)benzamides, the novel nicotinamides with 1-ethyl-4-methylhexahydro-1,4-diazepin ring were found to have potent 5-HT3 and dopamine D2 and D3 receptor antagonistic activities and to show weak central nervous system depression and extrapyramidal syndrome. After extensive SARs, AS-8112 was selected as a broad antiemetic agent.

• Authors: S Kato, I Fujiwara, N Yoshida
• Journal: Medicinal research reviews (Med Res Rev) Vol. 19 Issue 1 Pg. 25-73 (Jan 1999) ISSN: 0198-6325 [Print] United States
• PMID: 9918193 (Publication Type: Journal Article, Review)

Chemical References

• Antiemetics
• Gastrointestinal Agents
• Receptors, Serotonin
• Serotonin Antagonists

Topics

• Animals
• Antiemetics (chemical synthesis, metabolism, pharmacology)
• Drug Design
• Gastrointestinal Agents (chemical synthesis, metabolism, pharmacology)
• Molecular Structure
• Receptors, Serotonin (metabolism)
• Serotonin Antagonists (chemical synthesis, metabolism, pharmacology)
• Structure-Activity Relationship