title: Synthesis and structure-activity relationship studies in serotonin 5-HT(1A) receptor agonists based on fused pyrrolidone scaffolds.
abstract: 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.
authors: Dipartimento Farmaco Chimico Tecnologico and European Research Centre for Drug Discovery and Development, Università degli Studi di Siena, Via A. Moro, 53100 Siena, Italy. andrea.cappelli@unisi.it
authors: Andrea
authors: A
authors: Cappelli
authors: Monica
authors: M
authors: Manini
authors: Salvatore
authors: S
authors: Valenti
authors: Federica
authors: F
authors: Castriconi
authors: Germano
authors: G
authors: Giuliani
authors: Maurizio
authors: M
authors: Anzini
authors: Simone
authors: S
authors: Brogi
authors: Stefania
authors: S
authors: Butini
authors: Sandra
authors: S
authors: Gemma
authors: Giuseppe
authors: G
authors: Campiani
authors: Gianluca
authors: G
authors: Giorgi
authors: Laura
authors: L
authors: Mennuni
authors: Marco
authors: M
authors: Lanza
authors: Antonio
authors: A
authors: Giordani
authors: Gianfranco
authors: G
authors: Caselli
authors: Ornella
authors: O
authors: Letari
authors: Francesco
authors: F
authors: Makovec
mesh_terms: D000818:Animals; D019540:Area Under Curve; D006801:Humans; D007408:Intestinal Absorption; D008024:Ligands; D008297:Male; D008657:Metabolic Clearance Rate; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011760:Pyrrolidinones / Q000737:chemistry*; D011869:Radioligand Assay; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D011760:Pyrrolidinones; D044406:Receptors, Serotonin, 5-HT3; D058825:Serotonin 5-HT1 Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A