Deconstructing 14-phenylpropyloxymetopon: minimal requirements for binding to mu opioid receptors

Bioorg Med Chem. 2012 Jul 15;20(14):4556-63. doi: 10.1016/j.bmc.2012.05.006. Epub 2012 May 11.

Abstract

A series of phenylpropyloxyethylamines and cinnamyloxyethylamines were synthesized as deconstructed analogs of 14-phenylpropyloxymetopon and analyzed for opioid receptor binding affinity. Using the Conformationally Sampled Pharmacophore modeling approach, we discovered a series of compounds lacking a tyrosine mimetic, historically considered essential for μ opioid binding. Based on the binding studies, we have identified the optimal analogs to be N-methyl-N-phenylpropyl-2-(3-phenylpropoxy)ethanamine, with 1520 nM, and 2-(cinnamyloxy)-N-methyl-N-phenethylethanamine with 1680 nM affinity for the μ opioid receptor. These partial opioid structure analogs will serve as the novel lead compounds for future optimization studies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ethylamines / chemical synthesis
  • Ethylamines / chemistry*
  • Models, Molecular
  • Morpholines / chemistry*
  • Protein Binding
  • Receptors, Opioid, mu / chemistry
  • Receptors, Opioid, mu / metabolism*

Substances

  • 14-phenylpropoxymetopon
  • Ethylamines
  • Morpholines
  • Receptors, Opioid, mu