期刊
JOURNAL OF PHARMACY AND PHARMACOLOGY
卷 64, 期 8, 页码 1099-1106出版社
WILEY-BLACKWELL
DOI: 10.1111/j.2042-7158.2012.01500.x
关键词
5-HT4 receptor agonists; 5-methoxyindole derivatives; gastrointestinal tract; human colon; intestinal smooth muscle
资金
- National Health and Medical Research Council of Australia (NHMRC)
- Monash University Research Fund
- Faculty of Pharmacy and Pharmaceutical Sciences, Monash University
Objectives The aim was to examine the biological activity of 5-methoxytryptamine derivatives at the 5-hydroxytryptamine (5-HT)4 receptor to explore the effect of substitution on the aliphatic amine of the 5-methoxyamine scaffold. Methods Three compounds were tested for affinity at the 5-HT4 receptor by radioligand binding and functional activity using guinea-pig ileum and human colon circular muscle preparations and also in the mouse whole gut transit test. Key findings The three compounds all had agonist properties at the 5-HT4 receptor but their efficacy differed in the different functional tests. Compound 3 had the highest affinity for the 5-HT4 receptor and was a full agonist at relaxing human colon circular muscle with efficacy closest to 5-HT. Compounds 1 and 2 were partial agonists in this assay with lower efficacies; compound 2 was a full agonist in the guinea-pig ileum assay whereas compound 3 was a partial agonist. Compounds 1 and 2 also showed activity in the mouse gut transit assay while compound 3 had no activity. Conclusions Of the compounds tested, compound 3 was the most promising 5-HT4 receptor agonist and the results highlight the value of using human tissue in functional tests when assessing compounds for potential activity.
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