title: Synthesis and pharmacological effects of the enantiomers of the N-phenethyl analogues of the ortho and para e- and f-oxide-bridged phenylmorphans.
abstract: The N-phenethyl analogues of (1R*,4aR*,9aS*)-2-phenethyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2,3-c]pyridin-6-ol and 8-ol and (1R*,4aR*,9aR*)-2-phenethyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2.3-c]pyridin-6-ol and 8-ol, the ortho- (43) and para-hydroxy e- (20), and f-oxide-bridged 5-phenylmorphans (53 and 26) were prepared in racemic and enantiomerically pure forms from a common precursor, the quaternary salt 12. Optical resolutions were accomplished by salt formation with suitable enantiomerically pure chiral acids or by preparative HPLC on a chiral support. The N-phenethyl (-)- para-e enantiomer (1S,4aS,9aR-(-)-20) was found to be a mu-opioid agonist with morphine-like antinociceptive activity in a mouse assay. In contrast, the N-phenethyl (-)-ortho-f enantiomer (1R,4aR,9aR-(-)-53) had good affinity for the mu-opioid receptor (K(i) = 7 nM) and was found to be a mu-antagonist both in the [(35)S]GTP-gamma-S assay and in vivo. The molecular structures of these rigid enantiomers were energy minimized with density functional theory at the level B3LYP/6-31G* level, and then overlaid on a known potent mu-agonist. This superposition study suggests that the agonist activity of the oxide-bridged 5-phenylmorphans can be attributed to formation of a seven membered ring that is hypothesized to facilitate a proton transfer from the protonated nitrogen to a proton acceptor in the mu-opioid receptor.
authors.affiliation: Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse, National Institutes of Health, MD 20852, USA.
authors.forename: Josef
authors.initials: J
authors.lastname: Zezula
authors.forename: Lisa
authors.initials: L
authors.lastname: Singer
authors.forename: Anna K
authors.initials: AK
authors.lastname: Przybył
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hashimoto
authors.forename: Christina M
authors.initials: CM
authors.lastname: Dersch
authors.forename: Richard B
authors.initials: RB
authors.lastname: Rothman
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Deschamps
authors.forename: Yong Sok
authors.initials: YS
authors.lastname: Lee
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; D000882:Haplorhini; D051379:Mice; D008956:Models, Chemical; D015394:Molecular Structure; D009019:Morphinans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology; D010100:Oxygen / Q000737:chemistry*; D010626:Phenylethyl Alcohol / Q000737:chemistry; D011789:Quantum Theory; D013237:Stereoisomerism
chemical_list: D009019:Morphinans; D009292:Narcotic Antagonists; C042531:phenylmorphan; D010626:Phenylethyl Alcohol; D010100:Oxygen