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首页> 外文期刊>Life sciences >Conversion of delta-, kappa- and mu-receptor selective opioid peptide agonists into delta-, kappa- and mu-selective antagonists.
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Conversion of delta-, kappa- and mu-receptor selective opioid peptide agonists into delta-, kappa- and mu-selective antagonists.

机译：将δ，κ和μ受体选择性阿片肽激动剂转化为δ，κ和μ选择性拮抗剂。

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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 delta antagonists. Most successful was the development of kappa antagonists derived from dynorphin A (Dyn A), including the highly potent and selective kappa-antagonist [(2S)-Mdp(1)]Dyn A(1-11)-NH(2) (dynantin) and the enzymatically stable octapeptide analogue [(2S)-Mdp(1),MeArg(7),D-Leu(8)]Dyn A(1-8)-NH(2). The (2S)-Mdp(1)-analogues of dynorphin B and alpha-neoendorphin also were kappa antagonists and may be useful as pharmacological tools in studies of kappa receptor subtypes. Finally, the Dhp(1)-analogues of the mu-selective cyclic enkephalin analogue H-Tyr-c[N(epsilon ),N(beta)-carbonyl-D-Lys(2),Dap(5)]enkephalinamide and of endomorphin-2 were moderately potent mu opioid antagonists.
机译：阿片类激动剂肽的Tyr（1）残基的2'，6'-二甲基取代和带正电荷的N末端氨基的缺失或甲基的取代已被证明代表了转化阿片类药物的一般结构修饰肽激动剂变成拮抗剂。这种转化需要合成包含3-（2,6-二甲基-4-羟基苯基）丙酸（Dhp）或（2S）-2-甲基-3-（2,6-二甲基-4-羟基苯基）的阿片肽类似物）丙酸[（2S）-Mdp]代替Tyr（1）。使用这种方法，将δ，κ和μ选择性阿片肽激动剂肽成功转化为相应的δ，κ和μ选择性拮抗剂，从而经常保持或什至提高了受体的选择性。因此，δ-选择性环脑啡肽类似物H-Tyr-c [D-Pen-Gly-Phe（pF）-Pen] -Phe-OH的两个（2S）-Mdp（1）-类似物被证明是有效的，选择性δ拮抗剂。最成功的是衍生自强啡肽A（Dyn A）的kappa拮抗剂，包括高效和选择性的kappa拮抗剂[（2S）-Mdp（1）] Dyn A（1-11）-NH（2）（dynantin ）和酶稳定的八肽类似物[（2S）-Mdp（1），MeArg（7），D-Leu（8）] Dyn A（1-8）-NH（2）。强啡肽B和α-新内啡肽的（2S）-Mdp（1）-类似物也是κ拮抗剂，可用作研究κ受体亚型的药理学工具。最后，μ选择性环状脑啡肽类似物H-Tyr-c [N（epsilon），Nβ-羰基-D-Lys（2），Dap（5）]脑啡肽的Dhp（1）-类似物内啡肽2是中等有效的μ阿片类拮抗剂。

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