Gastrointestinal motility responses to the S and R enantiomers of zacopride, a 5-HT4 agonist and 5-HT3 antagonist

Autor: Maida A. Virina, Dai-Chang Yang, Bela Goldstin, Alan E. Moormann, Daniel L. Flynn, R F Loeffler, G. W. Gullikson
Rok vydání: 1992
Předmět:
Zdroj: Drug Development Research. 26:405-417
ISSN: 1098-2299
0272-4391
DOI: 10.1002/ddr.430260404
Popis: Zacopride is an antiemetic agent whose (S) and (R) stereoisomers demonstrate differential pharmacology at 5-HT3 receptors, emphasizing the importance of pharmacologic profiling of each enantiomer of a racemic drug mixture. Characterization of the gastrointestinal motility-enhancing activities of the enantiomers relative to their 5-HT3 antagonist properties was done both in vivo and in vitro. In dogs at a dose of 0.3 mg/kg, IV, the (S) antipode was more active in stimulating gastric antral contractions and gastric emptying of a solid meal than (R) zacopride. The (S) enantiomer was also at least 10 times more potent in enhancing gastric emptying in rats. The potency of (S) zacopride at the putative prokinetic receptor (5-HT4) was 3.3 times greater than that of (R) zacopride in rat esophageal tunica muscularis mucosae strips. The greater potency of (S) zacopride over the (R) antipode for motility stimulation was also observed for its 5-HT3 antagonism in dogs. (S) zacopride almost completely blocked cisplatin emesis at 0.01 mg/kg, IV, while (R) zacopride was inactive. However, both enantiomers were more active as antiemetics than as prokinetics in the dog. More potent activity at the 5-HT3 than the 5-HT4 receptor was also demonstrated for both enantiomers in vitro. Additionally, in antagonizing 2-methyl-5-HT contractions in guinea pig ileum, the (S) antipode was again more potent than the (R). In summary, (S) zacopride is more potent than the (R) enantiomer for both 5-HT3 antagonism and prokinetic activity, with 5-HT3 antagonism, rather than motility enhancement (5-HT4 agonism), being the primary activity of both zacopride stereoisomers. © 1992 Wiley-Liss, Inc.
Databáze: OpenAIRE
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