MISSISSIPPI COBRE: PROJ 1: MITRAGYNINE BASED OPIOID LIGANDS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 米拉吉宁是从泰国传统中草药米拉吉宁中分离出来的一种木选择性阿片类激动剂。最近的研究表明，该化合物和已报道的类似物具有通过阿片受体介导的镇痛活性。然而，从结构比较的角度来看，这种新颖的结构类使它们与已知的u和阿片配体相比很有趣。计划在这里开展的工作，结合化学合成、分子模拟、配基结合研究和体内行为模式，研究了米特拉宁识别和与阿片受体结合的分子基础。我们假设，三尖杉碱的结构可以作为设计和合成亚型选择性阿片受体配体的模板，通过阐明药效团，可以实现结构新颖的合成阿片配体。实现这一点将极大地提高对这些结构新颖的化合物与阿片受体相互作用的认识，并有助于开发和了解这些配体的潜在治疗作用。这项工作将通过以下步骤来完成：1)优化提取和纯化程序，2)确定米曲吉宁与阿片受体结合的分子基础，3)鉴定米曲吉宁和7-羟基米曲吉宁的药效团，4)研究米曲吉宁及其类似物的体内活性。预计将确定将米拉吉宁作为设计亚型选择性配体的新阿片模板的潜在用途及其作为阿片剂滥用疗法的潜在研究用途。此外，这项工作将为进一步深入了解米曲宁及其衍生物的药理活性机制提供依据。

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.