Further studies of tyrosine surrogates in opioid receptor peptide ligands
Further studies of tyrosine surrogates in opioid receptor peptide ligands
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DOI：
10.1016/j.bmcl.2007.01.092
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发表时间：
2007-05-01
影响因子：
2.7
通讯作者：
DeHaven, Robert N.
中科院分区：
文献类型：
--
作者：
Dolle, Roland E.;Michaut, Mathieu;DeHaven, Robert N.
制备了一系列含有修饰的N-末端酪氨酸（Tyr）残基的阿片肽配体，并针对克隆的人μ、δ和κ阿片受体进行了评价。这一工作扩展了最近发现的（S）-4-羧酰胺苯丙氨酸（Cpa）是一种有效的酪氨酸生物电子等排体。含有带负电荷的官能团代替酪氨酸的酚羟基的氨基酸缺乏受体亲和力，而Tyr与（S）-4-氨基苯丙氨酸的交换是适度成功的。含有新氨基酸（（S）-4-甲酰胺基-2，6-二甲基苯丙氨酸（Cdp）和（S）-β-（2-氨基苯并[d]噻唑-6-基）丙氨酸（阿坝））的肽在三种受体上显示出与母体配体相当的结合（Ki）和功能（EC 50）曲线。UP代表在总体活性方面表现最好的Tyr替代物，而Cpa和阿坝显示出对δ受体的微妙倾向。(c)2007爱思唯尔有限公司版权所有。
A series of opioid peptide ligands containing modified N-terminal tyrosine (Tyr) residues was prepared and evaluated against cloned human mu, delta, and kappa opioid receptors. This work extends the recent discovery that (S)-4-carboxamidophenylalanine (Cpa) is an effective tyrosine bioisostere. Amino acids containing negatively charged functional groups in place of tyrosine's phenolic hydroxyl lacked receptor affinity, while exchange of Tyr for (S)-4-aminophenylalanine was modestly successful. Peptides containing the new amino acids, (S)-4-carboxamido-2,6-dimethylphenylalanine (Cdp) and (S)-beta-(2-aminobenzo[dlthiazol-6-yl)alanine (Aba), displayed binding (K-i) and functional (EC50) Profiles comparable to the parent ligands at the three receptors. UP represents the best performing Tyr surrogate in terms of overall activity, while Cpa and Aba show a subtle proclivity toward the delta receptor. (c) 2007 Elsevier Ltd. All rights reserved.