Synthesis and evaluation of 4-substituted piperidines and piperazines as balanced affinity μ opioid receptor (MOR) agonist/δ opioid receptor (DOR) antagonist ligands

Bioorg Med Chem Lett. 2014 Jan 15;24(2):548-51. doi: 10.1016/j.bmcl.2013.12.021. Epub 2013 Dec 11.

Abstract

In this letter, we describe a series of 4-substituted piperidine and piperazine compounds based on tetrahydroquinoline 1, a compound that shows balanced, low nanomolar binding affinity for the mu opioid receptor (MOR) and the delta opioid receptor (DOR). We have shown that by changing the length and flexibility profile of the side chain in this position, binding affinity is improved at both receptors by a significant degree. Furthermore, several of the compounds described herein display good efficacy at MOR, while simultaneously displaying DOR antagonism. The MOR agonist/DOR antagonist has shown promise in the reduction of negative side effects displayed by selective MOR agonists, namely the development of dependence and tolerance.

Keywords: Mixed function opioids; Opioid peptidomimetics.

Publication types

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

MeSH terms

  • Animals
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Drug Evaluation, Preclinical / methods
  • Piperazines / chemical synthesis*
  • Piperazines / metabolism
  • Piperidines / chemical synthesis*
  • Piperidines / metabolism
  • Protein Binding / physiology
  • Receptors, Opioid, delta / antagonists & inhibitors*
  • Receptors, Opioid, delta / metabolism
  • Receptors, Opioid, mu / agonists*
  • Receptors, Opioid, mu / metabolism

Substances

  • Piperazines
  • Piperidines
  • Receptors, Opioid, delta
  • Receptors, Opioid, mu