Synthesis and biological evaluation of compact, conformationally constrained bifunctional opioid agonist - neurokinin-1 antagonist peptidomimetics

Eur J Med Chem. 2015 Mar 6:92:64-77. doi: 10.1016/j.ejmech.2014.12.033. Epub 2014 Dec 19.

Abstract

A reported mixed opioid agonist - neurokinin 1 receptor (NK1R) antagonist 4 (Dmt-D-Arg-Aba-Gly-(3',5'-(CF3)2)NMe-benzyl) was modified to identify important features in both pharmacophores. The new dual ligands were tested in vitro and subsequently two compounds (lead structure 4 and one of the new analogues 22, Dmt-D-Arg-Aba-β-Ala-NMe-Bn) were selected for in vivo behavioural assays, which were conducted in acute (tail-flick) and neuropathic pain models (cold plate and von Frey) in rats. Compared to the parent opioid compound 33 (without NK1R pharmacophore), hybrid 22 was more active in the neuropathic pain models. Attenuation of neuropathic pain emerged from NK1R antagonism as demonstrated by the pure NK1R antagonist 6. Surprisingly, despite a lower in vitro activity at NK1R in comparison with 4, compound 22 was more active in the neuropathic pain models. Although potent analgesic effects were observed for 4 and 22, upon chronic administration, both manifested a tolerance profile similar to that of morphine and cross tolerance with morphine in a neuropathic pain model in rat.

Keywords: Acute pain; Hybrid peptides; NK1R antagonism; Neuropathic pain; Opioid agonism; Tolerance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Cell Line
  • Cricetulus
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molecular Conformation
  • Neurokinin-1 Receptor Antagonists / pharmacology*
  • Peptidomimetics / chemical synthesis*
  • Peptidomimetics / chemistry
  • Rats
  • Rats, Wistar
  • Receptors, Neurokinin-1 / metabolism
  • Receptors, Opioid / agonists*

Substances

  • Neurokinin-1 Receptor Antagonists
  • Peptidomimetics
  • Receptors, Neurokinin-1
  • Receptors, Opioid