Synthesis and biological evaluation of bivalent cannabinoid receptor ligands based on hCB2R selective benzimidazoles reveal unexpected intrinsic properties |
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| Institution: | 1. Pharmazeutische und Medizinische Chemie, Institut für Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universität Würzburg, Am Hubland, D-97074 Würzburg, Germany;2. Lehrstuhl für Pharmazeutische Chemie I, Institut für Pharmazie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany;3. Lehrstuhl für Pharmazeutische Biologie, Institut für Pharmazie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany;1. Kazan (Volga Region) State University, Kremlevskaya Str. 18, 420008 Kazan, Russian Federation;2. A.E. Arbuzov Institute of Organic and Physical Chemistry of Kazan Scientific Centre of RAS, Arbuzov Str. 8, 420088 Kazan, Russian Federation;3. Kazan State Medical Academy, Mushtary Str. 11, 420010 Kazan, Russian Federation;1. Johns Hopkins University, Department of Chemistry, Baltimore, CA 21218, United States;2. Kongju National University, Department of Chemistry, 182, Shinkwan-dong, Kongju, Chungnam 314-701, Republic of Korea;1. University of Novi Sad, Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovi?a 3, 21000 Novi Sad, Serbia;2. Oncology Institute of Vojvodina, Faculty of Medicine, University of Novi Sad, Put Dr Goldmana 4, 21204 Sremska Kamenica, Serbia;3. University of Novi Sad, Faculty of Sciences, Department of Biology and Ecology, Trg Dositeja Obradovi?a 2, 21000 Novi Sad, Serbia;1. Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036, India;2. Sophisticated Analytical Instrumentation Facility, Indian Institute of Technology Madras, Chennai 600036, India;1. Department of Organic Chemistry, College of Chemistry, Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing University of Chemical Technology, Beijing 100029, China;2. College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang 473061, China;3. School of Food and Chemical Engineering, Beijing Technology and Business University, Beijing 100048, China |
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| Abstract: | The design of bivalent ligands targeting G protein-coupled receptors (GPCRs) often leads to the development of new, highly selective and potent compounds. To date, no bivalent ligands for the human cannabinoid receptor type 2 (hCB2R) of the endocannabinoid system (ECS) are described. Therefore, two sets of homobivalent ligands containing as parent structure the hCB2R selective agonist 13a and coupled at different attachment positions were synthesized. Changes of the parent structure at these positions have a crucial effect on the potency and efficacy of the ligands. However, we discovered that bivalency has an influence on the effect at both cannabinoid receptors. Moreover, we found out that the spacer length and the attachment position altered the efficacy of the bivalent ligands at the receptors by turning agonists into antagonists and inverse agonists. |
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| Keywords: | Bivalent ligand Cannabinoid receptor Benzimidazole |
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