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-HT3 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-HT1AR.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► A new series of 5-HT1A receptor ligands has been designed. ► Two compounds showed 5-HT1AR affinity values in the low nanomolar range. ► The SAR data have been rationalized by docking studies. ► Profiling assays revealed for two close congeners a divergent binding pattern. ► In functional studies, the compounds showed clear-cut agonist-like profiles.