CONFORMATION-SELECTIVITY RELATIONS OF OPIOID PEPTIDES

本建议的长远目标是阐明 活性所必需的结构和构象特征 阿片受体，主要强调δ阿片受体 受体的 这样的解释，除了加深我们的理解， 阿片类药物作用的分子基础，将大大有助于设计 具有更多选择性药理作用的类似物， 具有重要的临床意义。 实现这一目标的拟议办法 目的涉及合成，药理学评价， 合理设计的与三个相关的类似物的构象分析 已经开发的高度δ受体选择性阿片肽 由首席调查员。 此外，结构相关的 类似物，其代表了对μ受体选择性的显著引导 将被追捕。 这些系列类似物之间的相关性， 活性与结构和构象将允许确定 这些关键特征与特定阿片样物质的活性一致， 受体的 构象分析将在很大程度上依赖于现代NMR技术。 在 为了利用这些NMR提供的全部信息内容， 实验中，有必要将立体定向 氘代氨基酸，以允许完全分配共振 产生于所研究的肽中的双排质子（或碳）。 特别重要的是测量质子间的核 奥佛豪泽效应（NOE）和质子间距离的测定 这些NOE。 这些距离将被用作约束条件 对于符合 NMR数据。 约束结构的能量最小化 这些质子间的距离以及不受约束的结构将是 执行。 这些结构的能量的比较将解决 方法的合理性，并可能提供对约束力的洞察力 能量学

The long term objective of this proposal is the elucidation of the structural and conformational features necessary for activity at specific opioid receptors with major emphasis placed upon the delta opioid receptor. Such elucidation, in addition to furthering our understanding of the molecular basis of opioid action, would greatly aid the design of analogs with more selective pharmacological actions which may prove to be a great clinical significance. The proposed approach for achieving this objective involves the synthesis, pharmacological evaluation, and conformational analysis of rationally designed analogs related to three highly delta receptor selective opioid peptides which have been developed by the principal investigator. Additionally, a structurally related analog which represents a significant lead toward mu receptor selectivity will be pursued. Correlation, among these series of analogs, of opioid activity with structure and conformation will allow the determination of those key features consistent with activity at a specific opioid receptor. Conformational analyses will rely heavily on modern NMR techniques. In order to utilize the full informational content available from these NMR experiments, it will be necessary to incorporate stereospecifically deuterated amino acids so as to allow complete assignment of resonances arising from diasteriotopic protons (or carbons) in the peptides studied. Of particular importance will be the measurement of interproton nuclear Overhauser effects (NOE) and the determination of interproton distances from these NOEs. These distances will then be utilized as constraints for distance geometry calculations of conformations consistent with the NMR data. Energy minimization of structures constrained to adhere to these interproton distances as well as unconstrained structures will be performed. Comparison of the energies of these structures will address the reasonableness of the approach and may provide insight into binding energetics.