Agonist vs antagonist behavior of delta opioid peptides containing novel phenylalanine analogues in place of Tyr(1)

J Med Chem. 2009 Nov 12;52(21):6941-5. doi: 10.1021/jm9004913.

Abstract

The novel phenylalanine analogues 4'-[N-((4'-phenyl)phenethyl)carboxamido]phenylalanine (Bcp) and 2',6'-dimethyl-4'-[N-((4'-phenyl)phenethyl)carboxamido]phenylalanine (Dbcp) were substituted for Tyr(1) in the delta opioid antagonist TIPP (H-Tyr-Tic-Phe-Phe-OH; Tic = tetrahydroisoquinoline-3-carboxylic acid). Unexpectedly, [Bcp(1)]TIPP was a potent, selective delta opioid agonist, whereas [Dbcp(1)]TIPP retained high delta antagonist activity. Receptor docking studies indicated similar binding modes for the two peptides except for the biphenylethyl moiety which occupied distinct receptor subsites. The dipeptide H-Dbcp-Tic-OH was a highly selective delta antagonist with subnanomolar delta receptor affinity.

Publication types

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

MeSH terms

  • Binding Sites
  • Ligands
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / chemistry
  • Protein Conformation
  • Receptors, Opioid, delta / agonists*
  • Receptors, Opioid, delta / antagonists & inhibitors*
  • Receptors, Opioid, delta / chemistry
  • Tyrosine / chemistry*

Substances

  • 2',6'-dimethyl-4'-(N-((4'-phenyl)phenethyl)carboxamido)phenylalanine-tetrahydroisoquinoline-3-carboxylic acid- phenylalanyl-phenylalanine
  • 4'-(N-((4'-phenyl)phenethyl)carboxamido)phenylalanyl-tetrahydroisoquinoline-3-carboxylic acid- phenylalanyl-phenylalanine
  • Ligands
  • Oligopeptides
  • Receptors, Opioid, delta
  • Tyrosine