Synthesis of iboga-like isoquinuclidines: Dual opioid receptors agonists having antinociceptive properties |
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| Affiliation: | 1. Neurobiology Department, CSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata 700032, India;2. Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India;1. A.E. Arbuzov Institute of Organic and Physical Chemistry, Russian Academy of Sciences, Kazan Scientific Center, Arbuzov Str. 8, 420088 Kazan, Russian Federation;2. Institut für Anorganische Chemie der Universität Leipzig Johannisallee 29, 04103 Leipzig, Germany;1. Department of Chemistry, Sanandaj Branch, Islamic Azad University, P.O. Box 618, Sanandaj, Iran;2. Chemistry Department, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran;3. Department of Chemistry, Faculty of Science, University of Kurdistan, P.O. Box 720, Sanandaj, Iran;1. Hacettepe University, Chemistry Department, 06800 Beytepe, Ankara, Turkey;2. Çankaya University, Central Campus, Non-Departmental Courses Coordinatorship, 06790 Etimesgut, Ankara, Turkey;1. INRA – Biopolymères Interactions Assemblages (UR1268), F-44300 Nantes, France;2. Mondelez International Biscuit Europe R&D, France;1. School of Chemistry and Chemical Engineering, University of South China, Hengyang 421001, China;2. Department of Chemistry & Institute of Biomedical Science, Fudan University, Shanghai 200433, China;3. Laboratory of Protein Structure and Function, University of South China, Hengyang 421001, China;1. Department of Medicinal Chemistry, Respiratory Inflammation and Autoimmunity Innovative Medicines, AstraZeneca R&D, Pepparedsleden 1, SE-431 83 Mölndal, Sweden;2. Department of Medicinal Chemistry, AstraZeneca R&D Lund, Scheelevägen 1, SE-221 87 Lund, Sweden |
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| Abstract: | Some novel iboga-analogues consisting of benzofuran moiety and dehydroisoquinuclidine ring connected by –CH2–, (CH2)2 and (CH2)3 linkers have been synthesized with the view to develop potential antinociceptive drugs. The compounds 14 and 21 showed binding at the μ-opioid receptor (MOR), while the compound 11a exhibited dual affinities at both MOR and κ-opioid receptor (KOR). MAP kinase activation indicated all three compounds have opioid agonistic properties. The presence of a double bond and endo-methylcarboxylate group in the dehydroisoquinuclidine ring and the benzofuran and methylene spacer appeared to be essential for opioid receptor binding. Further studies demonstrated 11a caused significant antinociception in mice in the hot-plate test which was comparable to that produced by morphine. The compound 11a was also found to be nontremorigenic unlike various iboga congeners. This study identifies a new pharmacophore which may lead to the development of suitable substitute of morphine in the treatment of pain. |
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| Keywords: | Iboga-analogues Isoquinuclidine Opioids Antinociceptive properties Morphine |
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