Novel Opioid Peptide Derived Antagonists Containing 3-(2,6-Dimethyl-4-Carbamoylphenyl)-Propanoic Acid (Dcp) in Place of Tyr

摘要

@@ All naturally occurring opioid peptides contain an N-terminal tyrosine residue which plays a key-role in the interaction with their receptors. The discovery of the enkephalins (H-Tyr-Gly-Gly-Phe-Met (or Leu)-OH)[1] prompted numerous structure-activity studies aimed at elucidating the structural requirements for opioid activity. In early work, it was demonstrated that the N-terminal amino group and the Tyr1 hydroxyl group in Met-enkephalin play a crucial role in the interaction with opioid receptors, as deletion of either one of these two moieties resulted in inactive or weakly active compounds[2,3]. These early findings discouraged structural modifications of the Tyr residue of opioid peptides for some time until, in 1992, it was demonstrated that replacement of the Tyr1 residue in the cyclic enkephalin analogue H-Tyr-c[D-Pen-Gly-Phe-D-Pen]OH (DPDPE) with 2',6'-dimethyltyrosine (Dmt) produced an increase in μ and 5 opioid receptor binding affinity by at least one order of magnitude[4]. A more recent interesting discovery was that 2',6'-dimethyl substitution of the Tyr1 residue of opioid agonist peptides and deletion of the N-terminal amino group resulted in potent opioid antagonists[5-7]. This was achieved by substitution of Tyr1 with 3-(2,6-dimethyl-4-hydroxyphenyl)-propanoic acid (Dhp) (Figure 1). Subsequently, stereoselective syntheses of the methylated Dhp analogues (2S)-2-methyl-3-(2,6-dimethyl-4-hydroxyphenyl)-propanoic acid [(2S)-Mdp][8) and (3S)-3-methyl-3-(2,6-dimethyl-4-hydroxyphenyl)-propanoic acid [(3S)-Mdp][9] were developed. Replacement of Tyr1 in opioid peptides with (25)-Mdp or (3S)-Mdp produced opioid antagonists with further improved potency[6,7,9].