Structure-guided design of new indoles as negative allosteric modulators (NAMs) of N-methyl-d-aspartate receptor (NMDAR) containing GluN2B subunit |
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| Institution: | 1. Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche ed Ambientali (CHIBIOFARAM) Università degli Studi di Messina, Viale Annunziata, I-98168 Messina, Italy;2. Dipartimento di Medicina Sperimentale e Clinica, Università Magna Graecia, Viale Europa Località Germaneto, I-88100 Catanzaro, Italy;1. Institut Curie-Centre de Recherche, F-91405 Orsay Cédex, France;2. Institut National de la Santé et de la Recherche Médicale (INSERM) U759, F-91405 Orsay Cédex, France;3. UMR9187-U1196, F-91405 Orsay Cédex, France;4. UMR CNRS 7203, Paris Cédex 05, France;5. ENS Ecole Normale Supérieure de Paris, Paris Cédex 05, France;6. Université Paris 6, Paris Cédex 05, France;1. Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA;2. Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA;1. Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK;2. Department of Chemistry, University of Balochistan, Suryab Road, Quetta, Pakistan;1. School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy;2. Dipartimento di Scienze per la Promozione della Salute e Materno-Infantile—Sezione di Farmacologia, Università di Palermo, 90127 Palermo, Italy;3. Department of Medical Biochemistry and Biophysics, Umeå University, SE-90187 Umeå, Sweden;4. Centro Interdipartimentale di Ricerca in Oncologia Clinica, Policlinico ‘P. Giaccone’, Università di Palermo, 90127 Palermo, Italy;5. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and Richard Roudebush VA Medical Center, Indianapolis, IN 46202, USA |
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| Abstract: | Negative allosteric modulators (NAMs) of GluN2B-containing NMDARs provide pharmacological tools for the treatment of chronic neurodegenerative diseases. Novel NAMs have been designed on the basis of computational studies focused on the ‘hit compound’ 3. This series of indoles has been tested in competition assay. Compounds 16 and 17 were the most active ligands (IC50 values of 83 nM and 71 nM, respectively) and they showed a potency close to that of reference compounds ifenprodil (1, IC50 = 47 nM) and 3 (IC50 = 25 nM). Furthermore, docking studies have been performed for active ligand 16 and the results were in a good agreement with biological data. |
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| Keywords: | Glutamate GluN2B/NMDA Synthesis Indoles Molecular docking |
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