Journal of Pharmacy and Pharmacology 2012-08-01

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

Ian M Coupar, Helen R Irving, David T Manallack, Yean Y Tan, Fadi Ayad, Juliana Di Iulio, Nathalie Tochon-Danguy, Magdy N Iskander

Index: J. Pharm. Pharmacol. 64(8) , 1099-106, (2012)

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Abstract

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.Three compounds were tested for affinity at the 5-HT(4) 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.The three compounds all had agonist properties at the 5-HT(4) receptor but their efficacy differed in the different functional tests. Compound 3 had the highest affinity for the 5-HT(4) 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.Of the compounds tested, compound 3 was the most promising 5-HT(4) receptor agonist and the results highlight the value of using human tissue in functional tests when assessing compounds for potential activity.© 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.