Synthesis and structure-activity relationship studies in serotonin 5-HT1A receptor agonists based on fused pyrrolidone scaffolds

A new class of serotonin 5-HT1A receptor ligands related to NAN-190, buspirone and aripiprazole has been designed using our potent 5-HT 3 receptor ligands as templates. The designed pyrrolidone derivatives 10a-n were prepared by means of the straightforward chemistry consisting in the reaction of the appropriate γ-haloester derivatives with the suitable arylpiperazinylalkylamines. The nanomolar 5-HT1A receptor affinity and the agonist-like profile shown by fused pyrrolidone derivatives 10k,m stimulated the rationalization of the interaction with an homology model of the 5-HT1A receptor and the evaluation of their selectivity profiles and the pharmacokinetic properties. Interestingly, the results of the profiling assays suggested for close congeners 10k,m a significantly divergent binding pattern with compound 10m showing an appreciable selectivity for 5-HT 1AR. © 2013 Elsevier Masson SAS. All rights reserved.