NEUROPEPTIDES--MOLECULAR MECHANISM OF ACTION

Deltorphin分子特征的特异性研究 类阿片肽利用了70多种合成类似物， 包括氨基酸替换，选择，D-氨基酸替换， 和衍生物，以研究“消息”和“地址”的贡献 结合现象中的结构域。 我们的数据支持这样的论点， 高亲和力和非凡的选择性的deltorphins为 δ受体需要具有以下特征的七肽：（1） N-末端序列内位置2处的a-D-氨基酸 Tyr-D-Xaa-Phe;（2）而Tyr 1和Phe 3是结合的关键残基 在所有三角洲海豚中，三角洲海豚A中的Leu 5是不可或缺的;（3）一种 适当定位的阴离子基团（Asp或Glu）对于高的生物活性是必需的。 尽管对于高选择性来说不需要负电荷本身， 亲和力结合，这表明δ亲和力涉及排斥 （4）C-末端酰胺基团的功能是结合 受体的配体或稳定分子内构象;和（5） 在“消息”和“地址”域中的修改差别地干扰 δ和μ亲和力。 特别地，D-氨基酸取代和 缺失类似物，例如，内部缺失和C-末端衍生 deltorphin A和C的六肽、五肽、四肽和三肽， C-末端酰胺或羧基官能团，降低δ选择性。 在 事实上，四肽和三肽是μ选择性的。 这些数据表明 “地址”结构域中特定氨基酸残基的性质是 关键在于结合性能、特征和 阿片肽的选择性，而“消息”域包含一个 mu位点的通用序列，对delta和mu都通用 受体。

Research into the specificity of the molecular features of the deltorphin class of opioid peptides utilized over 70 synthetic analogues, which included amino acid substitutions, elections, D-amino acid replacements, and derivatives, to study contributions of the "message" and "address" domains in the binding phenomenon. Our data support the contention that high affinity and extraordinary selectivity of the deltorphins for the delta receptor requires a heptapeptide with the following features: (1) a-D-amino acid in position 2 within the N-terminal sequence of Tyr-D-Xaa-Phe; (2) whereas Tyrl and Phe3 are crucial residues for binding in all deltorphins, Leu5 in deltorphin A was indispensable; (3) an appropriately positioned anionic group (Asp or Glu) is necessary for high selectivity although a negative charge per se is not required for high affinity binding, which suggests that delta affinity involves repulsion from mu sites; (4) a C-terminal amide group functions either in binding the ligand to the receptor or stabilizing Intramolecular conformation; and (5) modifications in the "message" and "address" domains differentially perturb delta and mu affinities. In particular, D-amino acid substitutions and deletion analogues, e.g., internal deletions and C-terminally derived hexa-, penta-, tetra-, and tripeptides of deltorphins A and C, with either C-terminal amide or carboxyl functions, decreased delta selectivity. In fact, tetra- and tripeptides were mu selective. These data indicate that the nature of the specific amino acid residues in the "address" domain are critical in definity of the binding properties, characteristics, and selectivity of the opioid peptides, while the "message" domain contains a general sequence for mu sites, which is universal to both delta and mu receptors.