CONFORMATIONAL ANALYSIS OF RECEPTOR SELECTIVE OPIOIDS

这一更新申请的具体目的仍然是确定 μ和δ阿片样物质所需的生物活性构象 受体。这一决定将包括确定 配体的药效基团，即，那些提供 能量有利的相互作用与互补位点的 受体，以及阐明之间的相对几何形状 这些团体。特别令人感兴趣的是结构和 区别μ和δ配体的构象差异。我们 方法采用实验（主要是NMR）和理论 技术来开发这些生物活性构象的模型， 从构象受限的受体获得的信息 在缺乏受体的情况下选择性配体。既然连 构象约束，环肽研究这里含有 剩余的灵活性，特别是在药效团元件，几个 低能量构象通常是可获得的，其中任何一种 可能是生物活性构象异构体。鉴定此 因此，生物活性构象需要在一组相关的 其中引入了进一步的构象限制的肽 插入到母体肽的柔性元件中。阿片相关性 这组类似物与能量可及的 构象空间的区域可用于每一个允许更现实的 生物活性构象的精细化。最近的克隆和 μ和δ受体的序列解析和识别， 它们共享G蛋白偶联受体的共同结构基序 超家族提出了希望，配体的分子细节- 受体的相互作用是可接近的。我们提出计划， μ和δ受体的结构模型，并使用 从我们的一系列的补充构象和药理学数据， 类似物来解开这些配体-受体相互作用的细节。

The specific aims of this renewal application remain the determination of the bioactive conformations required at both mu and delta opioid receptors. This determination will include the identification of the pharmacophoric groups of the ligand, i.e., those moieties which provide energetically favorable interactions with complementary sites of the receptor, as well as the elucidation of the relative geometry between these groups. Of particular interest will be structural and conformational differences which distinguish mu from delta ligands. Our approach employs both experimental (primarily NMR) and theoretical techniques to develop models of these bioactive conformations both upon information garnered from conformationally constrained, receptor selective ligands int he absence of receptor. Since even the conformationally constrained, cyclic peptides studied here contain residual flexibility, particularly in the pharmacophore elements, several low energy conformations will in general be accessible, any one of which may be the sought after bioactive conformer. Identification of this bioactive conformation, then, requires comparison among a set of related peptides in which further conformational constraints are incorporated into the flexible elements of the parent peptide. Correlation of opioid binding affinity of this set of analogs with the energetically accessible regions of conformational space available to each allows a more realistic elaboration of the bioactive conformation. The recent cloning and sequence elucidation of mu and delta receptor and the recognition that they share the common structural motif of the G-protein coupled receptor superfamily raises the hope that the molecular details of the ligand- receptor interaction may be accessible. We propose plans to develop structural models of the mu and delta receptors and to use the complementary conformational and pharmacological data from our series of analogs to unravel details of these ligand-receptor interactions.