title: Synthesis of iboga-like isoquinuclidines: Dual opioid receptors agonists having antinociceptive properties.
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.
authors.affiliation: Neurobiology Department, CSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata 700032, India.
authors.forename: Tuhin Suvro
authors.initials: TS
authors.lastname: Banerjee
authors.affiliation: Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India.
authors.forename: Sibasish
authors.initials: S
authors.lastname: Paul
authors.affiliation: Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India. Electronic address: ocss5@iacs.res.in.
authors.forename: Surajit
authors.initials: S
authors.lastname: Sinha
authors.affiliation: Neurobiology Department, CSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata 700032, India. Electronic address: sdas@iicb.res.in.
authors.forename: Sumantra
authors.initials: S
authors.lastname: Das
mesh_terms: D000701:Analgesics, Opioid / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002460:Cell Line; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009020:Morphine / Q000627:therapeutic use; D010146:Pain / Q000188:drug therapy*; D011812:Quinuclidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D030014:Tabernaemontana / Q000737:chemistry; D014202:Tremor / Q000188:drug therapy
chemical_list: D000701:Analgesics, Opioid; D011812:Quinuclidines; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D009020:Morphine
keywords: Antinociceptive properties; Iboga-analogues; Isoquinuclidine; Morphine; Opioids