A novel cyclic enkephalin analogue with potent opioid antagonist activity

Abstract

The synthesis and in vitro activity profile of a potent opioid peptide antagonist lacking an N-terminal amino group are described. 2′,6′- Dimethyl substitution of the Tyr 1 residue in opioid agonist peptides and deletion of the N-terminal amino group, as achieved by replacement of Tyr 1 with 3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acid (Dhp), have been shown to produce opioid antagonists. To examine the effect of β-methylation of Dhp 1 in opioid peptides on the activity profile, stereoselective syntheses of (3S)- and (3R)-3-methyl-3-(2,6-dimethyl-4- hydroxyphenyl)propanoic acid [(3S)- and (3R)-Mdp] were carried out. In comparison with the cyclic parent antagonist peptide Dhp-c[D-Cys-Gly- Phe(pNO 2)-D-Cys]NH 2, the methylated analogue (3S)-Mdp-c[D-Cys-Gly-Phe(pNO 2)-D-Cys]NH 2 showed higher μ, δ and κ antagonist potencies in functional assays and higher binding affinities for μ, δ and κ opioid receptors (K i μ = 2.03 nM; K i δ = 2.34 nM; K i κ = 49.5 nM), whereas the corresponding (3R)-Mdp 1-analogue was less potent by 1-2 orders of magnitude. © 2004 Elsevier Ltd. All rights reserved.