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

Bioorg Med Chem. 2011 Jun 1;19(11):3434-43. doi: 10.1016/j.bmc.2011.04.028. Epub 2011 Apr 22.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Crystallography, X-Ray
  • Molecular Conformation
  • Morphinans / chemical synthesis
  • Morphinans / chemistry*
  • Morphinans / pharmacology
  • Narcotic Antagonists*
  • Oxides / chemistry*
  • Protein Binding
  • Receptors, Opioid / metabolism
  • Stereoisomerism

Substances

  • Morphinans
  • Narcotic Antagonists
  • Oxides
  • Receptors, Opioid
  • phenylmorphan