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Tryptophanol-derived oxazolopiperidone lactams: Identification of a hit compound as NMDA receptor antagonist
Affiliation:1. Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal;2. Pharmacology Unit, Faculty of Medicine and Health Sciences, Universitat Rovira i Virgili, c./St. Llorenç 21, 43201 Reus (Tarragona), Spain;3. Laboratory of Organic Chemistry, Faculty of Pharmacy and Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII, s/n, 08028 Barcelona, Spain;1. Departamento de Farmacología, Laboratorio de Farmacoquímica, Facultad de Farmacia, Universidad de Valencia, 46100 Burjassot, Valencia, Spain;2. Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Málaga, 29071 Málaga, Spain;3. Départament des Sciences Expérimentales, Institut de Recherches Servier, 92150 Suresnes, France;4. UMR CNRS 8076, LERMIT, Université Paris-Sud, Laboratoire de Pharmacognosie, UFR de Pharmacie, Châtenay-Malabry F-92296, France;5. Centro de Ecología Química Agrícola-Instituto Agroforestal Mediterraneo, UPV, Campus de Vera, Edificio 6C, 46022 Valencia, Spain;1. Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan;2. SHI Accelerator Service Co. Ltd, 5-9-11 Kitashinagawa, Shinagawa-ku, Tokyo 141-8686, Japan;1. Department of Microbiology, Nankai University, Tianjin, China;2. School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China;3. Tianjin Hospital, Tianjin, China;1. Department of Obstetrics, Gynecology and Reproductive Sciences, School of Medicine, University of Pittsburgh, Pittsburgh, PA;2. Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA;1. School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong Special Administrative Region;2. School of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing, PR China;3. Department of Chemistry, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong Special Administrative Region;4. Department of Applied Biology and Chemical Technology, Institute of Modern Chinese Medicine, The Hong Kong Polytechnic University, Hung Hom, Hong Kong Special Administrative Region;5. Department of Chemistry, South University of Science and Technology of China, Shenzhen, PR China
Abstract:N-Methyl-d-aspartate receptors (NMDAR) exacerbated activation leads to neuron death through a phenomenon called excitotoxicity. These receptors are implicated in several neurological diseases (e.g., Alzheimer and Parkinson) and thus represent an important therapeutic target. We herein describe the study of enantiopure tryptophanol-derived oxazolopiperidone lactams as NMDA receptor antagonists. The most active hit exhibited an IC50 of 63.4 μM in cultured rat cerebellar granule neurons thus being 1.5 fold more active than clinically approved NMDA antagonist amantadine (IC50 = 92 μM).
Keywords:Oxazolopiperidones  Tryptophanol  Neurodegenerative diseases  NMDAR antagonist
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