Assessment of the pharmacological properties of 5-methoxyindole derivatives at 5-HT4 receptors

Ian Michael Coupar, Helen Ruth Irving, David Thomas Manallack, Yean Yeow Tan, Fadi Ayad, Juliana L Di Iulio, Nathalie Tochon-Danguy, Magdy Naguib Iskander

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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.
Original languageEnglish
Pages (from-to)1099 - 1106
Number of pages8
JournalJournal of Pharmacy and Pharmacology
Issue number8
Publication statusPublished - 2012

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