Cyclic enkephalin analogues with exceptional potency and selectivity for delta-opioid receptors

J Med Chem. 1997 Nov 21;40(24):3957-62. doi: 10.1021/jm9704762.

Abstract

Superpotent and highly delta-opioid receptor selective cyclic peptides of the general formula H-Tyr-c[D-Pen-Gly-Phe(p-X)-Pen]-Phe-OH (where X = hydrogen or halogen) have been synthesized. In the binding assays the most selective and most potent compound is the p-bromophenyl-alanine-4 analogue (IC50 value = 0.19 nM, selectivity ratio = 21,000 for delta vs mu). In the GPI and MVD bioassays the most selective and most potent analogue is the p-fluoro-substituted analogue Tyr-[D-Pen-Gly-Phe(p-F)-Pen]-Phe-OH. In the MVD assay it has an exceptionally low IC50 value of 0.016 nM and a delta vs mu selectivity ratio of 45,000.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Analgesics / chemical synthesis*
  • Analgesics / pharmacology*
  • Animals
  • Enkephalins / chemical synthesis*
  • Enkephalins / pharmacology*
  • Guinea Pigs
  • Kinetics
  • Male
  • Peptides, Cyclic / chemical synthesis*
  • Peptides, Cyclic / pharmacology*
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Opioid, delta / drug effects
  • Receptors, Opioid, delta / metabolism*
  • Substrate Specificity

Substances

  • Analgesics
  • Enkephalins
  • Peptides, Cyclic
  • Receptors, Opioid, delta