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

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.