MISSISSIPPI COBRE: PROJ 1: MITRAGYNINE BASED OPIOID LIGANDS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 Mitragynine是从泰国传统草药Mitragyna speciosa中分离出的μ-选择性阿片激动剂。 最近的研究表明，这种化合物，并报告类似物，通过阿片受体介导的镇痛活性。 然而，新的结构类别使他们有趣的结构比较的角度来看，已知的μ和阿片样物质配体。计划在这里的工作，检查mitragynine识别和结合阿片受体的分子基础，使用化学合成，分子建模，配体结合研究和体内行为范例的组合。 我们推测，mitragynine的结构可以被用作模板的亚型选择性阿片受体配体的设计和合成，并通过阐明的药效团，结构新颖的合成阿片配体可以实现。 实现这一目标将大大提高这些结构新颖的化合物与阿片受体相互作用的知识，并促进这些配体的潜在治疗作用的开发和理解。 本论文的工作包括：1）优化提取和纯化工艺; 2）确定mitragynine与阿片受体结合的分子基础; 3）鉴定mitragynine和7-hydroxymitragynine的药效团; 4）研究mitragynine及其类似物的体内活性。预计将确定mitragynine作为一种新的阿片样物质模板用于设计亚型选择性配体及其作为阿片类药物滥用治疗的潜在用途。 此外，本工作将提供进一步了解的药理作用机制的mitragynine及其衍生物。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Mitragynine is a mu-selective opioid agonist isolated from the Thai traditional medicinal herb, Mitragyna speciosa. Recent studies have suggested this compound, and the reported analogs, posses analgesic activity mediated through opioid receptors. However, the novel structural class makes them interesting from a structural comparison standpoint to known mu and opioid ligands. The work planned here, examines the molecular basis of mitragynine recognition and binding to the opioid receptors using a combination of chemical synthesis, molecular modeling, and ligand binding studies and in vivo behavioral paradigms. We hypothesize that the structure of mitragynine can be utilized as a template for the design and synthesis of subtype-selective opioid receptor ligands and through elucidation of the pharmacophore, structurally novel synthetic opioid ligands can be realized. Accomplishing such will greatly improve the knowledge of interactions of these structurally novel compounds with opioid receptors and facilitate the development and understanding of the potential therapeutic roles of these ligands. This work will be accomplished by: 1) optimizing the extraction and purification procedures, 2) determining the molecular basis of mitragynine binding to opioid receptors, 3) identifying the pharmacophore of mitragynine and 7-hydroxymitragynine, and 4) investigating the in vivo activity of mitragynine and analogs. It is anticipated that the potential use of mitragynine as a new opioid template for the design of subtype selective ligands and their potential use for investigation as therapies for opiate abuse will be determined. Furthermore, this work will provide further insight into the mechanism of pharmacological activity of mitragynine and derivatives.