Discovery of tripeptide-derived multifunctional ligands possessing delta/mu opioid receptor agonist and neurokinin 1 receptor antagonist activities

Bioorg Med Chem Lett. 2015 Sep 1;25(17):3716-20. doi: 10.1016/j.bmcl.2015.06.030. Epub 2015 Jun 15.

Abstract

Several bifunctional peptides were synthesized and characterized based on the pentapeptide-derived ligand NP30 (1: Tyr-DAla-Gly-Phe-Gly-Trp-O-[3',5'-Bzl(CF3)2]). Modification and truncation of amino acid residues were performed, and the tripeptide-derived ligand NP66 (11: Dmt-DAla-Trp-NH-[3',5'-(CF3)2-Bzl]) was obtained based on the overlapping pharmacophore concept. The Trp(3) residue of ligand 11 works as a message residue for both opioid and NK1 activities. The significance lies in the observation that the approach of appropriate truncation of peptide sequence could lead to a tripeptide-derived chimeric ligand with effective binding and functional activities for both mu and delta opioid and NK1 receptors with agonist activities at mu and delta opioid and antagonist activity at NK1 receptors, respectively.

Keywords: Multifunctional ligands; Neutokinin-1 receptor antagonists; Opioid receptor agonists; Truncation of peptide sequence.

Publication types

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

MeSH terms

  • Animals
  • Chemistry Techniques, Synthetic
  • Drug Discovery
  • Drug Evaluation, Preclinical / methods
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • Humans
  • Inhibitory Concentration 50
  • Ligands
  • Neurokinin-1 Receptor Antagonists / chemistry
  • Neurokinin-1 Receptor Antagonists / pharmacology*
  • Peptides / chemistry*
  • Peptides / metabolism
  • Peptides / pharmacology*
  • Rats
  • Receptors, Opioid, delta / agonists*
  • Receptors, Opioid, mu / agonists*
  • Structure-Activity Relationship
  • Tryptophan / chemistry
  • Tryptophan / metabolism

Substances

  • Ligands
  • Neurokinin-1 Receptor Antagonists
  • Peptides
  • Receptors, Opioid, delta
  • Receptors, Opioid, mu
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • Tryptophan