Synthesis and pharmacological effects of the enantiomers of the N-phenethyl analogues of the ortho and para e- and f-oxide-bridged phenylmorphans

Josef Zezula; Lisa Singer; Anna K. Przybył; Akihiro Hashimoto; Christina M. Dersch; Richard B. Rothman; Jeffrey Deschamps; Yong Sok Lee; Arthur E. Jacobson; Kenner C. Rice

doi:10.1039/B803433H

Synthesis and pharmacological effects of the enantiomers of the N-phenethyl analogues of the ortho and para e- and f-oxide-bridged phenylmorphans†‡

Josef Zezula,§¶^a Lisa Singer,§^a Anna K. Przybył,§||^a Akihiro Hashimoto,§**^a Christina M. Dersch,^b Richard B. Rothman,^b Jeffrey Deschamps,^c Yong Sok Lee,^d Arthur E. Jacobson §^a and Kenner C. Rice §*^a

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* Corresponding authors

^a 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, MSC 9415, MD, USA
E-mail: kennerr@mail.nih.gov
Fax: +1(301) 402 0589
Tel: +1(301) 496 1856

^b Clinical Psychopharmacology Section, Chemical Biology Research Branch, National Institute on Drug Abuse, Addiction Research Center, National Institutes of Health, DHHS, Baltimore, MD, USA

^c Laboratory for the Structure of Matter, Naval Research Laboratory, Washington, DC, USA

^d Center for Molecular Modeling, Division of Computational Bioscience, CIT, National Institutes of Health, DHHS, Bethesda, MD, USA

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 μ-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 μ-opioid receptor (K_i = 7 nM) and was found to be a μ-antagonist both in the [³⁵S]GTP-γ-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 μ-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 μ-opioid receptor.

Organic & Biomolecular Chemistry

Synthesis and pharmacological effects of the enantiomers of the N-phenethyl analogues of the ortho and para e- and f-oxide-bridged phenylmorphans†‡

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Synthesis and pharmacological effects of the enantiomers of the N-phenethyl analogues of the ortho and para e- and f-oxide-bridged phenylmorphans

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