Endocannabinoid Active Sites as Therapeutic Targets

研究及相关-其他项目信息-项目概要/摘要 在这个计划项目更新申请中，我们建议从根本上扩展目前对 CB 1和CB 2大麻素受体的可变潜在功能调节。 在本报告所述期间，我们的工作导致制定了一些关键的战略， CB 1和CB 2大麻素受体的多种选择性激动剂和拮抗剂。我们还制作了 这两种受体结构的详细信息。基于这项基础工作的优势， 我们现在建议开发新的功能选择性工具，用于微调CB 1功能， 增强CB 2在体内的作用。我们的工作将产生早期候选人的发现和发展 新的治疗药物。在这次更新中，我们将阐明CB 1激动剂的功能选择性方面 并在CB 1处开发选择性增强内源性大麻素信号传导的正变构调节剂。我们也 我建议开发高选择性的CB 2激动剂，使CB 2的研究在体内，同时限制的贡献 与不良副作用相关的CB 1。此外，我们建议开发配体， 其作为CB 2的激活剂，同时也作为CB 1的拮抗剂。在体内使用这些化合物可能会导致 为炎症和纤维化疾病的药物开发奠定了基础。 我们的目标将通过合成药物类似物来实现。这些配体的设计将是 基于在当前资助期内开发的CB 1和CB 2受体的现有结构 并利用计算方法。这项工作将需要详细的分子药理学， 研究伴随CB 1和CB 2靶向突变的新型化合物的信号传导， 药理学信号分歧的机制基础。最有效的新化合物 将使用旨在探索潜在治疗价值的体内方法进行测定。 整个项目将提供大麻素受体信号传导的基础信息，并作为基础 为未来开发合理设计的，基于机制的治疗药物。

RESEARCH & RELATED - OTHER PROJECT INFORMATION - PROJECT SUMMARY/ABSTRACT In this Program Project renewal application, we propose to fundamentally expand current understanding of the variable potentially functional modulations of the CB1 and CB2 cannabinoid receptors. During this current period, our work has resulted in the development of a number of key pharmacologically diverse and selective agonists and antagonists for CB1 and CB2 cannabinoid receptors. We also produced detailed information on the structures of these two receptors. Based upon the strengths of this foundational work, we now propose to develop new functionally selective tools for fine tuning CB1 function and for selectively enhancing CB2 actions in vivo. Our work will generate early candidates for the discovery and development of new therapeutic medications. In this renewal, we will elucidate the functional selectivity aspect of CB1 agonists and develop positive allosteric modulators at CB1 that selectively enhance endocannabinoid signaling. We also propose to develop highly selective CB2 agonists to enable studies of CB2 in vivo while limiting the contributions of CB1 that have been associated with undesirable side effects. Additionally, we propose to develop ligands that act as activators of CB2 while also acting as CB1 antagonists. Using such compounds in vivo may lay the groundwork for the development of medications for inflammatory and fibrotic disorders. Our goals will be accomplished through the synthesis of druggable analogs. The design of these ligands will be based on existing structures of the CB1 and CB2 receptors that were developed during the current funding period and by utilizing computational approaches. The work will require detailed molecular pharmacology aimed at studying the signaling of novel compounds accompanied by targeted mutations in CB1 and CB2 to confirm mechanistic underpinnings of pharmacological divergences in signaling. The most efficient novel compounds will be assayed using in vivo approaches aimed at exploring potential therapeutic value. The overall project will provide foundational information on cannabinoid receptor signaling and serve as a basis for the future development of rationally designed, mechanism-based therapeutic medications.