Synthesis, Testing and Structure-Activity Studies on a Library of 5-HT4 Ligands

Amir      Hanna-Elias; David      T. Manallack; Alla      Levit; William      Nguyen; Fadi      Ayad; Glen      Perera; Marina      Shapiro; Helen      R. Irving; Ian      M. Coupar; Magdy      N. Iskander

Abstract

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 8.54 demonstrating very good affinity. These indole analogues were combined with 55 ligands that were previously produced in our laboratory to explore the structure-activity relationships of these 5-HT4 ligands. A CoMFA (Comparative Molecular Field Analysis) analysis was used to extend an earlier simple pharmacophore to suggest two new molecular features beyond the primary amino binding site. The pharmacophore confirmed that a newly described tetrahydroquinoline analogue was able to match the basic requirements of the model and the pharmacology of this molecule is provided in more detail.

Keywords: 5-HT4 ligands, radioligand binding, CoMFA, pharmacophore, molecular modelling, tetrahydroquinoline, gastroesophageal reflux disease, irritable bowel syndrome, TopCount Microplate Scintillation Counter, cisapride, metoclopramide, NMR spectrometer, Micromass Platform II single quadrupole mass spectrometer, electrospray, column chromatography