Conversion of δ-, κ- and μ-receptor selective opioid peptide agonists into δ-, κ- and μ-selective antagonists

被引:27
作者
Schiller, PW [1 ]
Weltrowska, G [1 ]
Nguyen, TMD [1 ]
Lemieux, C [1 ]
Chung, NN [1 ]
Lu, YX [1 ]
机构
[1] Clin Res Inst Montreal, Lab Chem Biol & Peptide Res, Montreal, PQ H2W 1R7, Canada
关键词
opioid peptide antagonists; delta opioid antagonists; kappa opioid antagonists; mu opioid antagonists; dynorphin A antagonists; dynantin; dynorphin B antagonist; alpha-neoendorphin antagonist;
D O I
10.1016/S0024-3205(03)00389-8
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
2',6-Dimethyl substitution of the Tyr(1) residue of opioid agonist peptides and deletion of the positively charged N-terminal amino group or its replacement with a methyl group has recently been shown to represent a general structural modification to convert opioid peptide agonists into antagonists. This conversion requires the syntheses of opioid peptide analogues containing either 3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acid (Dhp) or (2S)-2-methyl-3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acid [(2S)-Mdp] in place of Tyr(1). Using this approach, delta-, kappa- and mu-selective opioid peptide agonist peptides were successfully converted into corresponding delta-, kappa- and mu-selective antagonists, whereby receptor selectivity was often maintained or even improved. Thus, two (2S)-Mdp(1)-analogues of the delta-selective cyclic enkephalin analogue H-Tyr-c[D-Pen-Gly-Phe(pF)-Pen]-Phe-OH turned out to be potent and selective 6 antagonists. Most successful was the development Of K antagonists derived from dynorphin A (Dyn A), including the highly potent and selective kappa-antagonist [(2S)-Mdp(1)]Dyn A(1-11)-NH2 (dynantin) and the enzymatically stable octapeptide analogue [(2S)-Mdp(1),MeArg(7),D-Leu(8)]Dyn A(1-8)-NH2. The (2S)-Mdp(1)-analogues of dynorphin B and alpha-neoendorphin also were K antagonists and may be useful as pharmacological tools in studies Of K receptor subtypes. Finally, the Dhp(1)-analogues of the mu-selective cyclic enkephalin analogue H-Tyr-c[N,N[-carbonyl-D-Lys(2),Dap(5)]enkephalinamide and of endomorphin-2 were moderately potent mu opioid antagonists. (C) 2003 Elsevier Science Inc. All rights reserved.
引用
收藏
页码:691 / 698
页数:8
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