Stereoselective Synthesis 0f (3S)- and (3R)-3-Hydroxy-3-(2,6-Dimethyl-4-Hydroxyphenyl)Propanoic Acid and its Incorporation into a Cyclic Enkephalin Analogue
2',6'-dimethyl substitution of the Tyr1 residue of opioid agonist peptides and deletion of the N-terminal amino group have been shown to represent a general structural modification to convert opioid peptide agonists into antagonists . This conversion required the syntheses of opioid peptide analogues containing 3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acid (Dhp) in place of Tyr1. The cyclic enkephalin analogue Dhp-c[D-Cys-Gly-Phe(pNO2)-D-Cys]NH2 is a potent μ opioid antagonist and a less potent δ and k antagonist . An analogue of this peptide with β-methylated Dhp, (3S)-3-methyl-3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acid [(3S)-Mdp], in place of Dhp showed increased antagonist activity at all three receptors, whereas an analogue containing β-isopropyl-substituted Dhp [(3R)-Idp] turned out to be a mixed k agonist/μ antagonist . To further investigate the SAR at the β position of Dhp in the cyclic analogue, we examined the effect of substituting β-hydroxylated...
KeywordsPropanoic Acid Opioid Peptide Aldol Reaction Zinc Dust Stereoselective Synthesis
This work was supported by grants from the CIHR and the NIH.
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