title: Probes for narcotic receptor mediated phenomena. 43. Synthesis of the ortho-a and para-a, and improved synthesis and optical resolution of the ortho-b and para-b oxide-bridged phenylmorphans: compounds with moderate to low opioid-receptor affinity.
abstract: N-Phenethyl-substituted ortho-a and para-a oxide-bridged phenylmorphans have been obtained through an improved synthesis and their binding affinity examined at the various opioid receptors. Although the N-phenethyl substituent showed much greater affinity for μ- and κ-opioid receptors than their N-methyl relatives (e.g., K(i)=167 nM and 171 nM at μ- and κ-receptors vs >2800 and 7500 nM for the N-methyl ortho-a oxide-bridged phenylmorphan), the a-isomers were not examined further because of their relatively low affinity. The N-phenethyl substituted ortho-b and para-b oxide-bridged phenylmorphans were also synthesized and their enantiomers were obtained using supercritical fluid chromatography. Of the four enantiomers, only the (+)-ortho-b isomer had moderate affinity for μ- and κ-receptors (K(i)=49 and 42 nM, respectively, and it was found to also have moderate μ- and κ-opioid antagonist activity in the [(35)S]GTP-γ-S assay (K(e)=31 and 26 nM).
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, 5625 Fishers Lane, Room 4N03, Bethesda, MD 20892-9415, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: John E
authors.initials: JE
authors.lastname: Folk
authors.forename: Kejun
authors.initials: K
authors.lastname: Cheng
authors.forename: Muneaki
authors.initials: M
authors.lastname: Kurimura
authors.forename: Jason A
authors.initials: JA
authors.lastname: Deck
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: Arthur E
authors.initials: AE
authors.lastname: Jacobson
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
mesh_terms: D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D009019:Morphinans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009292:Narcotic Antagonists; D010087:Oxides / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D009019:Morphinans; D009292:Narcotic Antagonists; D010087:Oxides; C042531:phenylmorphan