Development of selective agents targeting serotonin 5HT 1A receptors with subnanomolar activities based on a coumarin core

A series of 18 new 5-[3-(4-aryl-1-piperazinyl)propoxy]coumarin derivatives from the corresponding bromoalkyl derivatives have been designed and synthesized by us using a microwave-assisted protocol. Radioligand binding assays of this series of compounds as well as a previously synthesized series of 17 structurally-similar compounds showed that six systems have very high affinities to the 5-HT receptor (0.3-1.0 nM) and good selectivity against the 5-HT receptor. Molecular docking, structural studies and structure-activity relationship studies were used to gain more insight into the atomistic details of ligand binding and rationalize the obtained results.