title: Discovery of mu-opioid selective ligands derived from 1-aminotetralin scaffolds made via metal-catalyzed ring-opening reactions.
abstract: A series of 1-aminotetralin scaffolds was synthesized via metal-catalyzed ring-opening reactions of heterobicyclic alkenes. Small libraries of amides and amines were made using the amino group of each scaffold as a handle. Screening of these libraries against human opioid receptors led to the identification of (S)-(S)-5.2a as a high-affinity selective mu ligand (IC(50)mu=5 nM, kappa=707 nM, delta=3,795 nM) displaying mu-agonist/antagonist properties due to its partial agonism (EC(50)=2.6 microM; E(max)=18%).
authors.affiliation: Davenport Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, Canada M5S 3H6.
authors.forename: Chris
authors.initials: C
authors.lastname: Dockendorff
authors.forename: Shujuan
authors.initials: S
authors.lastname: Jin
authors.forename: Madeline
authors.initials: M
authors.lastname: Olsen
authors.forename: Mark
authors.initials: M
authors.lastname: Lautens
authors.forename: Martin
authors.initials: M
authors.lastname: Coupal
authors.forename: Lejla
authors.initials: L
authors.lastname: Hodzic
authors.forename: Nathan
authors.initials: N
authors.lastname: Spear
authors.forename: Kemal
authors.initials: K
authors.lastname: Payza
authors.forename: Christopher
authors.initials: C
authors.lastname: Walpole
authors.forename: Mirosław J
authors.initials: MJ
authors.lastname: Tomaszewski
mesh_terms: D000701:Analgesics, Opioid / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002384:Catalysis; D020650:Combinatorial Chemistry Techniques; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D012238:Rhodium / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: D000701:Analgesics, Opioid; D008024:Ligands; D012238:Rhodium