title: A critical structural determinant of opioid receptor interaction with phenolic 5-phenylmorphans.
abstract: The opioid receptor binding affinities of N-methyl- and N-phenethyl-5-phenylmorphans with a meta-hydroxy substituent [3-(2-methyl-2-azabicyclo[3.3.1]non-5-yl)-phenol (1a), and 3-(2-phenethyl-2-azabicyclo[3.3.1]non-5-yl)-phenol (1b)] were compared with the affinities of four new ligands bearing an ortho- or para-hydroxyl substituent (2-(2-methyl-2-azabicyclo[3.3.1]non-5-yl)-phenol (2a) and 2-(2-phenethyl-2-azabicyclo[3.3.1]non-5-yl)-phenol (2b), 4-(2-methyl-2-azabicyclo[3.3.1]non-5-yl)-phenol (3a), and 4-(2-phenethyl-2-azabicyclo[3.3.1]non-5-yl)-phenol (3b)) that were synthesized from 2-bromoanisole or the known 2-methyl-5-phenyl-2-azabicyclo[3.3.1]nonane (13), respectively. The data indicated that either the electronic state of the phenolic ring is critical for the ligand's interaction with an opioid receptor, or that there must be a specific distance and angle for a hydrogen bond between the phenolic moiety and an amino acid in the binding domain that cannot be altered.
authors.affiliation: Laboratory of Medicinal Chemistry, Building 8, Room B1-23, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892-0815, USA.
authors.forename: In Jong
authors.initials: IJ
authors.lastname: Kim
authors.forename: Christina M
authors.initials: CM
authors.lastname: Dersch
authors.forename: Richard B
authors.initials: RB
authors.lastname: Rothman
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Jacobson
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
mesh_terms: D000818:Animals; D008024:Ligands; D009019:Morphinans / Q000737:chemistry*; D010636:Phenols / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011957:Receptors, Opioid / Q000737:chemistry / Q000378:metabolism*
chemical_list: D008024:Ligands; D009019:Morphinans; D010636:Phenols; D011957:Receptors, Opioid; C042531:phenylmorphan