[2 ',6 '-dimethyltyrosine]dynorphin A(1-11)-NH2 analogues lacking an N-terminal amino group: Potent and selective kappa opioid antagonists

Recent studies showed that dermorphin and enkephalin analogues containing t wo methyl groups at the 2 ' ,6 ' -positions of the Tyr(1) aromatic ring and lacking an N-terminal amino group were moderately potent delta and mu opio id antagonists. These results indicate that a positively charged N-terminal amino group may be essential for signal transduction but not for receptor binding and suggested that its deletion in agonist opioid peptides containi ng an N-terminal 2 ' ,6 ' -dimethyltyrosine (Dmt) residue may represent a g eneral way to convert them into antagonists. In an attempt to develop dynor phin A (Dyn A)-derived kappa opioid antagonists, we prepared analogues of [ Dmt(1)] Dyn A(1 - 11)-NH2 (1), in which the N-terminal amino group was eith er omitted or replaced with a methyl group. This was achieved by replacemen t of Tyr(1) with 3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acid (Dhp) or (2 S)-2-methyl-3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acid [(2S)-Mdp]. Comp ounds were tested in the guinea pig ileum and mouse vas deferens bioassays and in rat and guinea pig brain membrane receptor binding assays. All analo gues turned out to be potent kappa antagonists against Dyn A(1 - 13) and th e nonpeptide agonist U50,488 and showed only weak mu and delta antagonist a ctivity. The most potent and most selective kappa antagonist of the series was [(2S)-Mdp(1)]Dyn A(1 - 13)-NH2 (5, dynantin), which showed subnanomolar kappa antagonist potency against Dyn A(1-13) and very high kappa selectivi ty both in terms of its K-e values determined against kappa, mu, and delta agonists and in terms of its ratios of kappa, mu, and delta receptor bindin g affinity constants. Dynantin is the first potent and selective Dyn A-deri ved kappa antagonist known and may complement the non-peptide kappa antagon ists norbinaltorphimine and GNTI as a pharmacological tool in opioid resear ch.