Conformation - Selectivity Relations of Opioid Peptides

描述(申请人提供)：阿片类药物的合理设计需要详细了解阿片配体和阿片受体之间的精确相互作用，这些相互作用是特定阿片受体配体选择性的基础，并区分激动剂和拮抗剂的功能。在目前的授权期内，我们为实现这一认识所作的努力主要集中在改进和验证MU和德尔塔阿片受体(MOR和DOR)的配体/受体复合体模型，以及阐明区分与MOR和DOR结合的配体-受体相互作用的确切特征。在下一个授权期，我们建议通过应用从表现出高亲和力但非选择性的初始环状KOR(kappa阿片受体)多肽配体以及我们的MOR、DOR和KOR的配体-受体相互作用模型中获得的见解来扩大这些研究，以设计同一系列中通过KOR特异性受体相互作用实现KOR选择性的新KOR配体。我们还将开始使用环状五肽支架为孤儿受体ORL1进行基于结构的配体设计的类似过程。如果成功，这些研究将代表着为所有四类阿片受体基于结构相关的选择性配体设计的相当大的成就，其中两类(KOR和ORL1)通常只与较大的多肽配体结合。此外，我们将跟进令人兴奋的初步结果，指出决定疗效的特征。这些研究的成功将清楚地表明配体/受体相互作用模型的准确性，以及我们的方法对广泛的GPCR的适用性。最后，我们将继续努力，旨在将多肽衍生的药效团信息转移到具有更大潜力的模拟多肽支架上，作为可能的中枢神经系统活性临床药物。公共卫生相关性：阿片类药物与其蛋白质靶标的相互作用引发了这些药物的可取和不可取的影响。准确了解这些相互作用是设计和开发具有更多定制作用的阿片类药物的第一步，特别是减少耐受性、依赖倾向和滥用潜力的阿片类药物。

DESCRIPTION (provided by applicant): The rational design of opioid drugs requires a detailed understanding of the precise interactions between opioid ligand and opioid receptor that underlie ligand selectivity for a particular opioid receptor and that distinguish agonist from antagonist function. During the current grant period our efforts to gain that understanding have focused on the refinement and validation of models of ligand/receptor complexes for the mu and delta opioid receptors (MOR and DOR) and elucidation of the precise features of ligand-receptor interaction that differentiate binding to MOR and DOR. In the next grant period, we propose to extend these studies by applying the insights gained from initial cyclic KOR (kappa opioid receptor) peptide ligands that display high affinity but are nonselective, and from our ligand-receptor interaction models for MOR, DOR, and KOR to design new KOR ligands within the same series that achieve KOR selectivity through KOR-specific receptor interactions. We will also begin a similar process of structure based ligand design for the orphan receptor, ORL1, using a cyclic pentapeptide scaffold. If successful, these studies would represent the considerable achievement of structure-based design of structurally related selective ligands for all 4 classes of opioid receptors, two of which (KOR and ORL1) typically bind only larger peptide ligands. Further, we will follow-up exciting initial results that point to features that determine efficacy. Success in these studies would be a clear indicator of the accuracy of the ligand/receptor interaction models and the applicability of our approaches to a wide array of GPCRs. Finally, we will continue our efforts aimed at transferring peptide-derived pharmacophore information to peptidomimetic scaffolds that hold much greater potential as possible CNS active clinical agents. PUBLIC HEALTH RELEVANCE: The interaction of opioid drugs with their protein targets initiates the desirable and undesirable effects of these drugs. Gaining a precise understanding of these interactions is the first step toward the design and development of opioid drugs with more tailored actions, especially opioids with reduced tolerance, dependence liability, and abuse potential.