Marco, IsabelValhondo Falcón, MargaritaMartín-Fontecha Corrales, María Del MarVázquez Villa, María Del HenarDel Rio, JoaquinPlanas, AnnaSagredo Ezquioga, OnintzaRamos Atance, José AntonioTorrecillas, Iván R.Pardo, LeonardoFrechilla, DianaBenhamú Salama, BellindaLópez Rodríguez, María Luz2025-01-132025-01-132011-12-08Marco, I., Valhondo, M., Martı́n-Fontecha, M., Vázquez-Villa, H., Del Rı́o, J., Planas, A., Sagredo, O., Ramos, J. A., Torrecillas, I. R., Pardo, L., Frechilla, D., Benhamú, B., López-Rodrı́guez, M. L. New Serotonin 5-HT1A Receptor Agonists with Neuroprotective Effect against Ischemic Cell Damage. J. Med. Chem. 2011, 54 (23), 7986-79990022-262310.1021/jm2007886https://hdl.handle.net/20.500.14352/113955We report the synthesis of new compounds 4–35 based on structural modifications of different moieties of previously described lead UCM-2550. The new nonpiperazine derivatives, representing second-generation agonists, were assessed for binding affinity, selectivity, and functional activity at the 5-HT1A receptor (5-HT1AR). Computational β2-based homology models of the ligand–receptor complexes were used to explain the observed structure–affinity relationships. Selected candidates were also evaluated for their potential in vitro and in vivo neuroprotective properties. Interestingly, compound 26 (2-{6-[(3,4-dihydro-2H-chromen-2-ylmethyl)amino]hexyl}tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione) has been characterized as a high-affinity and potent 5-HT1AR agonist (Ki = 5.9 nM, EC50 = 21.8 nM) and exhibits neuroprotective effect in neurotoxicity assays in primary cell cultures from rat hippocampus and in the MCAO model of focal cerebral ischemia in rats.engAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/journal article1520-4804https://doi.org/10.1021/jm2007886https://pubs.acs.org/doi/10.1021/jm2007886restricted access547Serotonin 5-HT1A receptorAgonistsStructure–affinity relationshipsNeuroprotectionIschemic cell damageQuímica orgánica (Química)Química farmaceútica2306 Química Orgánica2390.01 Diseño. Síntesis y Estudio Nuevos Fármacos