CONFORMATIONAL ANALYSIS OF RECEPTOR SELECTIVE OPIOIDS

本次续签申请的具体目标仍是决心 Mu和Delta阿片类药物所需的生物活性构象 感受器。这一确定将包括识别 配体的药用基团，即那些能够提供 在能量上有利的相互作用与互补的位置 受体，以及它们之间的相对几何关系的阐明 这些团体。特别感兴趣的将是结构性和 区别u和三角洲配体的构象差异。我们的 方法采用了实验(主要是核磁共振)和理论两种方法 开发这些生物活性构象模型的技术 从构象受限的受体获得的信息 受体缺失时的选择性配体。因为即使是 这里研究的构象受限的环肽包括 残留灵活性，特别是在药效团元素中，几个 低能构象通常是可获得的，其中任何一种 可能是人们追捧的生物活性构象。这一点的识别 因此，生物活性构象需要比较一组相关的 含有进一步构象限制的多肽 进入母体多肽的柔性元件中。阿片类药物的相关性 这组类似物与能量可及的 可用于每个区域的构象空间允许更逼真 生物活性构象的阐述。最近的克隆和 Mu和Delta受体的序列分析及其识别 它们具有G蛋白偶联受体的共同结构基序 超家族带来了希望，配体的分子细节- 受体的相互作用可能是可获得的。我们提出了发展的计划 Mu和Delta受体的结构模型，并使用 我们的一系列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.