New Serotonin 5-HT1A Receptor Agonists with Neuroprotective Effect against Ischemic Cell Damage

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• 作者：Isabel Marco ; Margarita Valhondo ; Mar Martı ; ́ ; n-Fontecha ; Henar V谩zquez-Villa ; Joaquı ; ́ ; n Del Rı ; ́ ; o ; Anna Planas ; Onintza Sagredo ; Jos茅 A. Ramos ; Iv谩n R. Torrecillas ; Leonardo Pardo ; Diana Frechilla ; Bellinda Benham煤 ; Marı ; ́ ; a L. L贸pez-Rodrı ; ́ ; guez
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：December 8, 2011
• 年：2011
• 卷：54
• 期：23
• 页码：7986-7999
• 全文大小：576K
• 年卷期：v.54,no.23(December 8, 2011)
• ISSN：1520-4804

文摘

We report the synthesis of new compounds 4鈥?b>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-HT_1A receptor (5-HT_1AR). Computational 尾₂-based homology models of the ligand鈥搑eceptor complexes were used to explain the observed structure鈥揳ffinity 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-HT_1AR agonist (K_i = 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.