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Title: A novel cyclic enkephalin analogue with potent opioid antagonist activity
Authors: Weltrowska, G.
Lu, Y. 
Lemieux, C.
Chung, N.N.
Schiller, P.W.
Issue Date: 20-Sep-2004
Citation: Weltrowska, G., Lu, Y., Lemieux, C., Chung, N.N., Schiller, P.W. (2004-09-20). A novel cyclic enkephalin analogue with potent opioid antagonist activity. Bioorganic and Medicinal Chemistry Letters 14 (18) : 4731-4733. ScholarBank@NUS Repository.
Abstract: The synthesis and in vitro activity profile of a potent opioid peptide antagonist lacking an N-terminal amino group are described. 2′,6′- Dimethyl substitution of the Tyr 1 residue in opioid agonist peptides and deletion of the N-terminal amino group, as achieved by replacement of Tyr 1 with 3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acid (Dhp), have been shown to produce opioid antagonists. To examine the effect of β-methylation of Dhp 1 in opioid peptides on the activity profile, stereoselective syntheses of (3S)- and (3R)-3-methyl-3-(2,6-dimethyl-4- hydroxyphenyl)propanoic acid [(3S)- and (3R)-Mdp] were carried out. In comparison with the cyclic parent antagonist peptide Dhp-c[D-Cys-Gly- Phe(pNO 2)-D-Cys]NH 2, the methylated analogue (3S)-Mdp-c[D-Cys-Gly-Phe(pNO 2)-D-Cys]NH 2 showed higher μ, δ and κ antagonist potencies in functional assays and higher binding affinities for μ, δ and κ opioid receptors (K i μ = 2.03 nM; K i δ = 2.34 nM; K i κ = 49.5 nM), whereas the corresponding (3R)-Mdp 1-analogue was less potent by 1-2 orders of magnitude. © 2004 Elsevier Ltd. All rights reserved.
Source Title: Bioorganic and Medicinal Chemistry Letters
ISSN: 0960894X
DOI: 10.1016/j.bmcl.2004.06.077
Appears in Collections:Staff Publications

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