A Novel Cyclic Opioid Peptide Antagonist Containing a Hydroxy Group in Place of the N-Terminal Amino Function
Since a positively charged N-terminal amino group in opioid peptides is generally thought to be of crucial importance for their interaction with opioid receptors, it is of interest to determine the effect on biological activity of its elimination or replacement with other groups. Recently, we prepared a des-amino analogue of the potent cyclic β-casomorphin-derived peptide H-Dmt-c[D-Orn-2-Nal-D-Pro-Gly] (Dmt = 2′,6′-dimethyl-tyrosine) . The Dmt1-analogue was chosen as parent peptide because substitution of Dmt for Tyr1 in opioid peptides is known to generally result in significantly enhanced µ and δ opioid receptor binding affinities . The preparation of the des-amino peptide required the synthesis of 3-(4-hydroxy-2,6-dimethylphenyl)propanoic acid (Dhp) . Interestingly, Dhp-[D-Orn-2-Nal-D-Pro-Gly] turned out to be a δ and µ opioid antagonist with moderate receptor binding affinities, indicating that a positively charged N-terminal amino group is not a conditio sine qua non for binding to δ and µ opioid receptors. To further examine the role of the N-terminal amino group in opioid peptides on receptor binding and signal transduction, its replacement with a hydroxyl group is of interest. This can be achieved by replacement of Tyr1 with (2S)-2-hydroxy-3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acid [(2S)-Hdp]. Here we describe the syntheses of the (2S)-Hdp1- and (2R)-Hdp1-analogues of the potent cyclic opioid peptide agonist H-Tyr-c[D-Cys-Gly-Phe(pNO2)-D-Cys]NH2  and their in vitro opioid activity profiles in comparison with that of the corresponding des-amino analogue.
KeywordsHPLC Sulfide Hydroxyl Tyrosine Dimethyl
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