Pharmacophores of 5-HT4 Receptor Ligands: Experience of CERMN and Implications for Drug Design

The definitions of pharmacophores for 5-HT4 receptor agonists and antagonists are described in this review. These pharmacophores were keys in the design of new selective ligands for this receptor, starting generally from 5-HT3 receptor ligands. Our laboratory has defined two series of 5-HT4 receptor ligands through comparative analysis of pharmacophores associated with partial agonists at 5-HT3 receptors and antagonists at 5-HT4 receptors. For 5-HT4 receptor agonists, a new 3D-QSAR analysis was carried out leading to a pharmacophore which we compared to previous data. One of the main challenges for the study of 5-HT4 receptors is to obtain a clear definition of the pharmacological profile associated with the ligand derivatives. This is discussed in terms of the conformational space associated with the receptor as well as data from site-directed mutagenesis studies. Finally, all these results allow a more precise description of the pharmacophores and give interesting insights into the structural modifications that appear to be of pivotal importance for the activity of 5-HT4 receptor ligands.