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 limited derivatives, posses analgesic activity mediated through opioid receptor systems. However, the novel structural class make them interesting from a structural comparison standpoint to known mu and opioid ligands. The work planned here, examines the molecular basis to 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 nove 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) determining the molecular basis of mitragynine binding to opioid receptors, 2) Identification of the pharmacophore of mitragynine and 7-hydroxymitragynine, 3) developing structure based models of mitragynine recognition that explain the structure activity relationship of analogs, and 4) investigation of the ;n vivo activity of mitragynine and it's analogs. It is anticipated that the potential use of mitragynine as a new opioid template for the design of subtype selective iigands 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.
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