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-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.

Key Findings: The three compounds all had agonist properties at the 5-HT(4) receptor but their efficacy differed in the different functional tests.

Synthesis, testing and structure-activity studies on a library of 5-HT₄ ligands.

Several indole derivatives and analogues comprising a range of related structural classes were designed, synthesized and tested as ligands for the 5-HT₄ receptor. Within each series, binding experiments showed compounds with good affinity demonstrating high percentage displacement values at 1 µM. The most potent of these (20) had a pKi of 8.

Optimization of a pharmacophore model for 5-HT4 agonists using CoMFA and receptor based alignment.

Twenty two 5-HT4 agonists obtained from our laboratory and the recent literature were used to develop a CoMFA model to predict 5-HT4 agonist activity. Two models were produced and compared for predictivity, the first by alignments based on atom overlapping (model A) and the second by adding agonist binding site interacting points of the 5-HT4 receptor (model B). Comparison of the two models showed that the q2 value for model A was 0.