title: Essential structure of opioid κ receptor agonist nalfurafine for binding to the κ receptor 2: synthesis of decahydro(iminoethano)phenanthrene derivatives and their pharmacologies.
abstract: To clarify the essential structures of an opioid κ receptor selective agonist, nalfurafine, for binding to the κ receptor, we designed and synthesized some nalfurafine derivatives and the decahydro(iminoethano)phenanthrene derivatives with a cyclohexene moiety as a surrogate for the phenol ring. In addition to the 6-amide side chain and the 17-nitrogen substituted by a cyclopropylmethyl group, the 4,5-epoxy ring, phenolic hydroxy group, and angular hydroxy group played important roles in eliciting the binding properties of nalfurafine but these three moieties were not indispensable for binding to the κ receptor. Moreover, the phenol ring was also not essential for the binding to the κ receptor, and the cyclohexene moiety would play an important role in fixing the conformation of decahydro(iminoethano)phenanthrene derivatives to effectively raise the amide side chain, rendering a conformation that resembled the active one of nalfurafine.
authors: Department of Medicinal Chemistry, School of Pharmacy, Kitasato University, Minato-ku, Tokyo, Japan. nagaseh@pharm.kitasato-u.ac.jp
authors: Hiroshi
authors: H
authors: Nagase
authors: Satomi
authors: S
authors: Imaide
authors: Shigeto
authors: S
authors: Hirayama
authors: Toru
authors: T
authors: Nemoto
authors: Hideaki
authors: H
authors: Fujii
mesh_terms: D053138:Cyclohexenes / Q000737:chemistry; D009019:Morphinans / Q000737:chemistry* / Q000378:metabolism; D010616:Phenanthrenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000378:metabolism; D013141:Spiro Compounds / Q000737:chemistry* / Q000378:metabolism
chemical_list: D053138:Cyclohexenes; D009019:Morphinans; D010616:Phenanthrenes; D017473:Receptors, Opioid, kappa; D013141:Spiro Compounds; C108819:kappa(2) opioid receptor; C052568:cyclohexene; C111212:TRK 820; C031181:phenanthrene