CONFORMATION - SELECTIVITY RELATIONS OF OPIOID PEPTIDES

描述：(申请人摘要) 拟议研究的主要长期目标是：1. 确定所需的精确结构和构象特征 用于识别Mu、Delta和kappa阿片受体的配基。2. 阐明给予个体阿片类药物选择性的特征 受体，要么通过额外的配体-受体相互作用在 或通过阻碍与不受欢迎的受体的结合来实现。3. 识别那些区分激动剂和激动剂的特征 对抗者。以及4.将所获得的信息用于设计 对三者各有选择性的高亲和力激动剂和拮抗剂 阿片受体。这里提出的研究扩展了用于 Mu和kappa的Delta阿片受体药效团模型 在当前赠与期内开发的选择性多肽先导以及 模拟多肽的结构可能导致Mu、Delta和 卡帕选择性类比。这种方法的突出之处是使用了新的 跨膜结构域结构模型的计算方法 Delta、Mu和kappa受体(以及一般的G蛋白偶联受体) 协助设计新的阿片类药物配基并补充实验 (核磁共振谱和X射线衍射)和理论(分子 力学计算)配体本身的构象分析。 除了针对阿片受体及其受体的研究 配体、阿片类药物相关新型配体的设计与合成 孤儿受体(ORLI)的研究将基于对 组合文库与孤儿受体跨膜模型的建立 域。这些研究将与理查德·霍顿合作完成 托里·派恩斯分子研究所的。

DESCRIPTION: (Applicant's Abstract) The primary, long-term goals of the proposed research are: 1. The determination of the precise structural and conformational features required for ligand recognition at, mu, delta, and kappa opioid receptors. 2. The elucidation of those features which impart selectivity at individual opioid receptors, either through additional ligand-receptor interactions at the favored receptor or by impeding binding to the disfavored receptors. 3. The identification of those features that distinguish agonists from antagonists. and 4. The use of the information so gained for the design of high affinity agonists and antagonists selective for each of the three opioid receptors. The studies proposed here extend the approach used to develop a delta opioid receptor pharmacophore model to mu and kappa selective peptide leads developed in the current grant period as well as to peptidomimetic structures which represent possible leads to mu, delta, and kappa selective analogs. Prominent in the approach is the use of new methods for calculating structural models of the transmembrane domain of delta, mu, and kappa receptors (and G-protein coupled receptors, in general) to assist in the design of new opioid ligands and to complement experimental (NMR spectroscopy and x-ray diffraction) and theoretical (molecular mechanics calculations) conformational analysis of the ligands themselves. In addition to investigations directed toward the opioid receptors and their ligands, the design and synthesis of novel ligands for the opioid-related orphanin receptor (ORLI) will be pursued based upon analysis of combinatorial libraries and modeling of the orphanin receptor transmembrane domain. These studies will be done in collaboration with Richard Houghten of Torrey Pines Institute for Molecular Studies.