Redefining the structure-activity relationships of 2,6-methano-3-benzazocines. Part 8. High affinity ligands for opioid receptors in the picomolar Ki range: oxygenated N-(2-[1,1'-biphenyl]-4-ylethyl) analogues of 8-CAC

Bioorg Med Chem Lett. 2012 Dec 15;22(24):7340-4. doi: 10.1016/j.bmcl.2012.10.081. Epub 2012 Oct 27.

Abstract

N-[2-(4'-methoxy[1,1'-biphenyl]-4-yl)ethyl]-8-CAC (1) is a high affinity (K(i)=0.084 nM) ligand for the μ opioid receptor and served as the lead compound for this study. Analogues of 1 were made in hopes of identifying an SAR within a series of oxygenated (distal) phenyl derivatives. A number of new analogues were made having single-digit pM affinity for the μ receptor. The most potent was the 3',4'-methylenedioxy analogue 18 (K(i)=1.6 pM).

Publication types

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

MeSH terms

  • Cyclazocine / analogs & derivatives*
  • Cyclazocine / chemical synthesis
  • Cyclazocine / chemistry
  • Cyclazocine / pharmacology
  • Dose-Response Relationship, Drug
  • Humans
  • Ligands
  • Molecular Structure
  • Oxygen / chemistry*
  • Receptors, Opioid, mu / agonists*
  • Receptors, Opioid, mu / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Ligands
  • N-(2-(4'-methoxy(1,1'-biphenyl)-4-yl)ethyl)-8-carboxamidocyclazocine
  • Receptors, Opioid, mu
  • Cyclazocine
  • Oxygen