Search for New Cannabinoid Receptor Ligands

在发现有用的合成CB1和CB2激动剂和拮抗剂以及内源性食人素配体方面取得了很大进展。这些化合物作为研究工具的可用性极大地有助于研究受体在中枢神经系统相关和其他生理过程中的作用。最近大麻类化合物研究的一个持续重点是寻找可能具有抢手的治疗功能而没有显著副作用的新型拟大麻化合物。该项目的目标是通过在两个方面开展实验工作，为大麻素受体确定新的和有效的大麻素配体。在第一方面，我们将继续已经开始的工作，即鉴定现有的各种代谢物 激动剂和拮抗剂，并测试纯形式的代谢物的受体结合活性。这项工作背后的假设是，大麻素激动剂/拮抗剂的某些代谢产物可能会保留受体结合特性，并可能具有修改后的副作用。这一假设得到了我们实验室最近获得的结果的支持，这些结果表明WIN55212-2的两种代谢物具有很强的CB1结合能力。我们建议将代谢物的代谢和受体结合活性的研究扩展到最近发现的三个大麻素配体。这部分实验的结果将提供两个重要问题的答案：代谢物中保留了多少结合亲和力，以及对 CB1和CB2保留在代谢产物中。在第二方面，我们寻求在选定的中草药成分中筛选拟大麻化合物，这些成分将被提取和分离用于受体结合分析。启动这项研究的基本原理是基于这样一个事实，即结构上不同的化合物，如氨基烷基吲哚和经典的大麻素，可以具有强大的受体结合活性。这意味着其他不同结构和来源的激动剂很可能存在。在用于抗炎治疗和慢性疼痛治疗的传统中草药中，可能会发现一种有前景的铅。我们的策略是使用从草药提取物中提取的部分层析制剂，并筛选结合活性。那些表现出高受体亲和力的化合物将接受进一步的纯化和结构阐明，直到鉴定出与大麻素受体结合有关的个别化合物。新型仿大麻分子的发现可能会为大麻类化合物的研究开辟新的场所。这些天然化合物及其合成衍生物的可获得性将大大有助于我们理解受体的机制，并衍生可能的治疗应用。

Much progress has been made in discovering useful synthetic CB1 and CB2 agonists and antagonists, as well as the endogenous cannibinoid ligands. The availability of these compounds as research tools has greatly aided in the study of receptor roles in the CNS-related and other physiological processes. An ongoing focus in recent cannabinoid research has been to find novel cannabimimetic compounds that may have the sought-after therapeutic functions without significant side effects. The goal of this project is to identify new and potent cannabinoid ligands for the cannabinoid receptors by conducting experimental work on two fronts. On the first front, we will continue the work already started, that of identifying the various metabolites of existing agonists and antagonists and testing the pure forms of the metabolites for receptor binding activities. The hypothesis behind this work is that certain metabolic products of cannabinoid agonists/antagonists will likely retain receptor-binding properties and have possible modified side effects. The hypothesis is supported by recent results obtained in our laboratory that show potent CB1 binding ability of two metabolites of WIN55212-2. We propose to extend the study of metabolism and receptor binding activities of metabolites to three recently found cannabinoid ligands. Results from this part of experiments will provide answers to two important questions: how much binding affinity is retained in the metabolites and how much selectivity for CB1 and CB2 is reserved in the metabolites. On the second front, we seek to screen for cannabimimetic compounds in selected Chinese herbal components that will be extracted and isolated for receptor binding assays. The rationale for initiating this study is based upon the fact that structurally distinct compounds such as the aminoalkylindoles and classical cannabinoids can possess potent receptor binding activities. This implies that other agonists of different structures and origins may well exist. A promising lead may be found in traditional Chinese herbal medicine that has been used for anti-inflammatory therapy and chronic pain management. Our strategy is to use portions of chromatographic preparations from the herbal extracts and screen for binding activities. Those showing high receptor affinities will be subjected to further purification and structural elucidation until individual compounds responsible for cannibinoid receptor binding are identified. Discovery of novel types of cannabimimetic molecules may open new venues for cannabinoid research. Availability of such naturally occurring compounds and their synthetic derivatives will contribute significantly to our understanding of the receptor mechanism and to derive possible therapeutic applications.