title: Probes for narcotic receptor mediated phenomena. Part 42: synthesis and in vitro pharmacological characterization of the N-methyl and N-phenethyl analogues of the racemic ortho-c and para-c oxide-bridged phenylmorphans.
abstract: A new synthesis of N-methyl and N-phenethyl substituted ortho-c and para-c oxide-bridged phenylmorphans, using N-benzyl- rather than N-methyl-substituted intermediates, was used and the pharmacological properties of these compounds were determined. The N-phenethyl substituted ortho-c oxide-bridged phenylmorphan(rac-(3R,6aS,11aS)-2-phenethyl-2,3,4,5,6,11a-hexahydro-1H-3,6a-methanobenzofuro[2,3-c]azocin-10-ol (12)) was found to have the highest μ-opioid receptor affinity (K(i)=1.1 nM) of all of the a- through f-oxide-bridged phenylmorphans. Functional data ([³⁵S]GTP-γ-S) showed that the racemate 12 was more than three times more potent than naloxone as an μ-opioid antagonist.
authors.affiliation: Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse and The National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892-9415, USA. jheeeee@gmail.com
authors.forename: Jin-Hee
authors.initials: JH
authors.lastname: Kim
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Deschamps
authors.forename: Richard B
authors.initials: RB
authors.lastname: Rothman
authors.forename: Christina M
authors.initials: CM
authors.lastname: Dersch
authors.forename: John E
authors.initials: JE
authors.lastname: Folk
authors.forename: Kejun
authors.initials: K
authors.lastname: Cheng
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Jacobson
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
mesh_terms: D018360:Crystallography, X-Ray; D008968:Molecular Conformation; D009019:Morphinans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D009292:Narcotic Antagonists; D010087:Oxides / Q000737:chemistry*; D011485:Protein Binding; D011957:Receptors, Opioid / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D009019:Morphinans; D009292:Narcotic Antagonists; D010087:Oxides; D011957:Receptors, Opioid; C042531:phenylmorphan