Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P46098 (5-HT3 receptor)
 2,290 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The serotonin 5-HT3 receptor antagonist effects of DAT-582, the (R) enantiomer of AS-5370 ((+/-)-N-[1-methyl-4-(3-methyl-benzyl)hexahydro-1H-1,4-diazepin-6- yl]-1H- indazole-3-carboxamide dihydrochloride), and its antipode were compared with those of AS-5370 and existing 5-HT3 receptor antagonists. In anesthetized rats, DAT-582 antagonized 2-methyl-5-HT-induced bradycardia with an ED50 value of 0.25 microgram/kg i.v., whereas the (S) enantiomer was without effect even at 1000 micrograms/kg i.v. In antagonizing the bradycardia, DAT-582 was as potent as granisetron, slightly more potent than AS-5370, and 2, 5 and 18 times more potent than ondansetron, ICS 205-903 and renzapride, respectively, although it was less potent than zacopride. DAT-582 inhibited cisplatin (10 mg/kg i.v.)-induced emesis in ferrets with an ED50 value of 3.2 micrograms/kg i.v. twice. The antiemetic activity of DAT-582 was more potent than that of the existing 5-HT3 receptor antagonists examined, except zacopride. In contrast, the (S) enantiomer had little effect at 1000 micrograms/kg i.v. twice. In isolated guinea-pig ileum, DAT-582 inhibited 5-HT-induced contractions with an IC50 value of 91 nM, whereas the (S) enantiomer hardly inhibited them even at 1000 nM. These results suggest that DAT-582, the (R) enantiomer of AS-5370, potently and selectively blocks 5-HT3 receptors.
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PMID:5-HT3 receptor antagonist effects of DAT-582, (R) enantiomer of AS-5370. 142 31

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.
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PMID:Nitrogen-containing heteroalicycles with serotonin receptor binding affinity: development of gastroprokinetic and antiemetic agents. 991 93