title: 4β-Methyl-5-(3-hydroxyphenyl)morphan opioid agonist and partial agonist derived from a 4β-methyl-5-(3-hydroxyphenyl)morphan pure antagonist.
abstract: In previous studies we reported that addition of 7α-acylamino groups to N-phenylpropyl-4β-methyl-5-(3-hydroxyphenyl)morphan (4) led to compounds that were pure opioid receptor antagonists. In contrast to these findings we report in this study that addition of a 7α-amino (5a), 7α-alkylamino (5b-e), or 7α-dialkylamino (5f-h) group to 4 leads to opioid receptor ligands with varying degrees of agonist/antagonist activity. The 7α-amino and 7α-methylamino analogues were full agonists at the μ and δ receptors and antagonists at the κ receptor. The 7α-cyclopropylmethylamino analogue 5h was a full agonist at the μ receptor with weaker agonist activity at the δ and κ receptors. Whereas the addition of a 7α-acylamino group to the pure nonselective opioid receptor antagonist N-phenylpropyl-4β-methyl-5-(3-hydroxyphenyl)morphan (4) led to κ selective pure opioid receptor antagonist, the addition of a 7α-amino, 7α-alkylamino, or 7α-dialkylamino group to 4 leads to opioid ligands that are largely μ or δ agonist with mixed agonist/antagonist properties.
authors.affiliation: Center for Organic and Medicinal Chemistry, Research Triangle Institute , P.O. Box 12194, Research Triangle Park, North Carolina 27709, United States.
authors.forename: F Ivy
authors.initials: FI
authors.lastname: Carroll
authors.forename: Moses G
authors.initials: MG
authors.lastname: Gichinga
authors.forename: John D
authors.initials: JD
authors.lastname: Williams
authors.forename: Eyal
authors.initials: E
authors.lastname: Vardy
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.forename: S Wayne
authors.initials: SW
authors.lastname: Mascarella
authors.forename: James B
authors.initials: JB
authors.lastname: Thomas
authors.forename: Hernán A
authors.initials: HA
authors.lastname: Navarro
mesh_terms: D053961:Azabicyclo Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D009292:Narcotic Antagonists; D011957:Receptors, Opioid / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D053961:Azabicyclo Compounds; D009292:Narcotic Antagonists; D011957:Receptors, Opioid