beta-Methyl Substitution of Cyclohexylalanine in Dmt-Tic-Cha-Phe Peptides Results in Highly Potent delta Opioid Antagonists

摘要

The opioid peptide TIPP (H-Tyr-Tic-Phe-Phe-OH,Tic:1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) was substituted with Dmt (2',6'-dimethyltyrosine) and a new unnatural amino acid,beta-MeCha (beta-methyl-cyclohexylalanine).This double substitution led to a new series of opioid peptides displaying subnanomolar delta antagonist activity and mu agonist or antagonist properties depending on the configuration of the beta-MeCha residue.The most promising analog,H-Dmt-Tic-(2S,3S)-beta-MeCha-Phe-OH was a very selective delta antagonist both in the mouse vas deferens (MVD) assay (K_e = 0.241 +- 0.05 nM) and in radioligand binding assay (K_i~(delta) = 0.48 +- 0.05 nM,K_i~(mu)/K_i~(delta) = 2800).The epimeric peptide H-Dmt-Tic-(2S,3R)-beta-MeCha-Phe-OH and the corresponding peptide amide turned out to be mixed partial mu agonist/delta antagonists in the guinea pig ileum and MVD assays.Our results constitute further examples of the influence of Dmt and beta-methyl substitution as well as C-terminal amidation on the potency,selectivity,and signal transduction properties of TIPP related peptides.Some of these compounds represent valuable pharmacological tools for opioid research.