[2′,6′-dimethyltyrosine]dynorphin A(1-11)-NH2 analogues lacking an N-terminal amino group:: Potent and selective κ opioid antagonists
[2′,6′-dimethyltyrosine]dynorphin A(1-11)-NH2 analogues lacking an N-terminal amino group:: Potent and selective κ opioid antagonists
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DOI：
10.1021/jm0101186
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发表时间：
2001-09-13
影响因子：
7.3
通讯作者：
Schiller, PW
中科院分区：
文献类型：
--
作者：
Lu, YX;Nguyen, TMD;Schiller, PW
最近的研究表明，在 Tyr(1) 芳香环的 2',6'-位上含有两个甲基且缺乏 N 末端氨基的皮吗啡和脑啡肽类似物是中等效力的 delta 和 mu 阿片拮抗剂。这些结果表明，带正电荷的 N 端氨基可能对于信号转导至关重要，但对于受体结合而言并非必需，并表明在含有 N 端 2',6'-二甲基酪氨酸 (Dmt) 残基的激动剂阿片肽中删除该氨基可能代表将其转化为拮抗剂的一般方法。为了开发强啡肽 A (Dyn A) 衍生的 κ 阿片类拮抗剂，我们制备了 [Dmt(1)] Dyn A(1 - 11)-NH2 (1) 的类似物，其中 N 末端氨基被省略或被甲基取代。这是通过用 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)丙酸 [(2S)-Mdp] 替换 Tyr(1) 来实现的。在豚鼠回肠和小鼠输精管生物测定以及大鼠和豚鼠脑膜受体结合测定中测试了化合物。所有类似物均被证明是针对 Dyn A(1 - 13) 和非肽激动剂 U50,488 的有效 κ 拮抗剂，并且仅表现出微弱的 mu 和 delta 拮抗剂活性。该系列中最有效和最具选择性的 kappa 拮抗剂是 [(2S)-Mdp(1)]Dyn A(1 - 13)-NH2 (5, dynantin)，它对 Dyn A(1-13) 表现出亚纳摩尔 kappa 拮抗剂效力，并且在针对 kappa、mu 和 delta 激动剂测定的 K-e 值以及 kappa、mu、和δ受体结合亲和力常数。 Dyntin 是已知的第一个有效且选择性的 Dyn A 衍生 kappa 拮抗剂，可以补充非肽 kappa 拮抗剂降比那托菲明和 GNTI 作为阿片类药物研究的药理学工具。
Recent studies showed that dermorphin and enkephalin analogues containing two methyl groups at the 2 ' ,6 ' -positions of the Tyr(1) aromatic ring and lacking an N-terminal amino group were moderately potent delta and mu opioid antagonists. These results indicate that a positively charged N-terminal amino group may be essential for signal transduction but not for receptor binding and suggested that its deletion in agonist opioid peptides containing an N-terminal 2 ' ,6 ' -dimethyltyrosine (Dmt) residue may represent a general way to convert them into antagonists. In an attempt to develop dynorphin A (Dyn A)-derived kappa opioid antagonists, we prepared analogues of [Dmt(1)] Dyn A(1 - 11)-NH2 (1), in which the N-terminal amino group was either omitted or replaced with a methyl group. This was achieved by replacement of Tyr(1) with 3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acid (Dhp) or (2S)-2-methyl-3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acid [(2S)-Mdp]. Compounds were tested in the guinea pig ileum and mouse vas deferens bioassays and in rat and guinea pig brain membrane receptor binding assays. All analogues turned out to be potent kappa antagonists against Dyn A(1 - 13) and the nonpeptide agonist U50,488 and showed only weak mu and delta antagonist activity. The most potent and most selective kappa antagonist of the series was [(2S)-Mdp(1)]Dyn A(1 - 13)-NH2 (5, dynantin), which showed subnanomolar kappa antagonist potency against Dyn A(1-13) and very high kappa selectivity both in terms of its K-e values determined against kappa, mu, and delta agonists and in terms of its ratios of kappa, mu, and delta receptor binding affinity constants. Dynantin is the first potent and selective Dyn A-derived kappa antagonist known and may complement the non-peptide kappa antagonists norbinaltorphimine and GNTI as a pharmacological tool in opioid research.