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Asymmetric synthesis and receptor activity of chiral simplified resiniferatoxin (sRTX) analogues as transient receptor potential vanilloid 1 (TRPV1) ligands
Affiliation:1. Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea;2. Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China;3. National Leading Research Lab of Molecular Modeling & Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Sciences and Global Top 5 Research Program, Ewha Womans University, Seoul 120-750, Republic of Korea;4. Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA;1. Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood Street, Chicago 60612, USA;2. Center for Pharmaceutical Biotechnology, College of Pharmacy, University of Illinois at Chicago, 900 S. Ashland Ave., Chicago, IL 60607, USA;3. Department of Medicinal Chemistry, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood Street, Chicago 60612, USA;1. Universidade Federal do Rio de Janeiro (UFRJ), Núcleo de Pesquisas de Produtos Naturais (NPPN), CCS, bloco H, Ilha do Fundão, Rio de Janeiro, RJ, Brazil;2. UFRJ, Instituto de Química, CT, Ilha do Fundão, Rio de Janeiro, RJ, Brazil;3. UFRJ, Instituto de Química, CT, Programa de Pós-Graduação em Bioquímica, Departamento de Bioquímica, Ilha do Fundão, Rio de Janeiro, RJ, Brazil;1. Department of Organic Chemistry, Institute of Chemical Sciences, Faculty of Science, P.J. Šafárik University, Moyzesova 11, 040 01 Košice, Slovak Republic;2. Department of Pharmacology, Faculty of Medicine, P.J. Šafárik University, SNP 1, 040 66 Košice, Slovak Republic;3. Division of Biological Sciences, Graduate School of Science, Frontier Research Center for Post-Genomic Science and Technology, Hokkaido University, Kita-ku, Sapporo 001-0021, Japan;4. Department of Analytical Chemistry, Institute of Chemical Sciences, Faculty of Science, P.J. Šafárik University, Moyzesova 11, 040 01 Košice, Slovak Republic
Abstract:The chiral isomers of the two potent simplified RTX-based vanilloids, compounds 2 and 3, were synthesized employing highly enantioselective PTC alkylation and evaluated as hTRPV1 ligands. The analysis indicated that the R-isomer was the eutomer in binding affinity and functional activity. The agonism of compound 2R was comparable to that of RTX. Docking analysis of the chiral isomers of 3 suggested the basis for its stereospecific activity and the binding mode of 3R.
Keywords:Vanilloid receptor 1  TRPV1 antagonist  Capsaicin  Resiniferatoxin  Molecular modeling
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