title: Opioid ligands with mixed properties from substituted enantiomeric N-phenethyl-5-phenylmorphans. Synthesis of a micro-agonist delta-antagonist and delta-inverse agonists.
abstract: Enantiomeric N-phenethyl-m-hydroxyphenylmorphans with various substituents in the ortho, meta or para positions of the aromatic ring in the phenethylamine side-chain (chloro, hydroxy, methoxy, nitro, methyl), as well as a pyridylethyl and a indolylethyl moiety on the nitrogen atom, were synthesized and their binding affinity to the mu-, delta-, and kappa-opioid receptors was examined. The higher affinity ligands were further examined in the [(35)S]GTPgammaS assay to study their function and efficacy. 3-((1R,5S)-(-)-2-(4-Nitrophenethyl)-2-aza-bicyclo[3.3.1]nonan-5-yl)phenol ((-)-) was found to be a mu-agonist and delta-antagonist in that functional assay and was about 50 fold more potent than morphine in vivo. 3-((1R,5S)-(-)-2-(4-Chlorophenethyl)-2-aza-bicyclo[3.3.1]nonan-5-yl)phenol ((-)-) and several other ligands displayed inverse agonist activity at the delta-opioid receptor. The absolute configuration of all of the reported compounds was established by chemical conversion of (-)- to 1R,5S-(-)-.HBr.
authors.affiliation: Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892-0815, USA. kr21f@nih.gov.
authors.forename: Kejun
authors.initials: K
authors.lastname: Cheng
authors.affiliation: Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892-0815, USA. kr21f@nih.gov.
authors.forename: In Jong
authors.initials: IJ
authors.lastname: Kim
authors.affiliation: Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892-0815, USA. kr21f@nih.gov.
authors.forename: Mei-Jing
authors.initials: MJ
authors.lastname: Lee
authors.affiliation: Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892-0815, USA. kr21f@nih.gov.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Adah
authors.affiliation: University of New England, College of Osteopathic Medicine, Biddeford, ME 04005, USA.
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Raymond
authors.affiliation: University of New England, College of Osteopathic Medicine, Biddeford, ME 04005, USA.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Bilsky
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Mario D
authors.initials: MD
authors.lastname: Aceto
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Everette L
authors.initials: EL
authors.lastname: May
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Louis S
authors.initials: LS
authors.lastname: Harris
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Coop
authors.affiliation: Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224, USA.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Dersch
authors.affiliation: Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224, USA.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Rothman
authors.affiliation: Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892-0815, USA. kr21f@nih.gov.
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Jacobson
authors.affiliation: Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892-0815, USA. kr21f@nih.gov.
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D008024:Ligands; D009019:Morphinans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000737:chemistry; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D009019:Morphinans; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu