Search for New Cannabinoid Receptor Ligands

在发现有用的合成CB 1和CB 2激动剂和拮抗剂以及内源性cannibinoid配体方面已经取得了很大进展。这些化合物作为研究工具的可用性极大地帮助了CNS相关和其他生理过程中受体作用的研究。最近大麻素研究的一个持续焦点是寻找新的大麻拟似化合物，这些化合物可能具有受欢迎的治疗功能，而没有显著的副作用。该项目的目标是通过在两个方面进行实验工作来确定大麻素受体的新的和有效的大麻素配体。在第一个方面，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，并有可能改变副作用。该假设得到了我们实验室最近获得的结果的支持，这些结果显示WIN 55212 -2的两种代谢产物具有强效的CB 1结合能力。我们建议将代谢产物的代谢和受体结合活性的研究扩展到三个最近发现的大麻素配体。这部分实验的结果将回答两个重要的问题：代谢物中保留了多少结合亲和力，以及代谢物的选择性有多大。 CB 1和CB 2保留在代谢产物中。在第二个方面，我们寻求筛选大麻拟化合物在选定的中草药成分，将被提取和分离的受体结合试验。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，可以拥有强大的受体结合活性。这意味着可能存在其他不同结构和来源的激动剂。一个有前途的铅可能会发现在传统的中草药，已用于抗炎治疗和慢性疼痛管理。我们的策略是使用来自草药提取物的部分色谱制剂并筛选结合活性。显示高受体亲和力的那些将进行进一步纯化和结构解析，直到鉴定出负责cannibinoid受体结合的单个化合物。发现新型的大麻模拟分子可能为大麻素研究开辟新的途径。这种天然存在的化合物及其合成衍生物的可用性将大大有助于我们对受体机制的理解，并获得可能的治疗应用。

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.