Search for New Cannabinoid Receptor Ligands

寻找新的大麻素受体配体

基本信息

批准号：
6727064
负责人：
Guangdi Wang
金额：
$ 8.18万
依托单位：
XAVIER UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2008-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6727064
关键词：
cannabinoid receptor cannabinoids drug discovery /isolation drug metabolism ligands mass spectrometry medicinal plants narcotic antagonists nuclear magnetic resonance spectroscopy plant extracts receptor binding stimulant /agonist tissue /cell culture

项目摘要

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.

在发现有用的合成 CB1 和 CB2 激动剂和拮抗剂以及内源性大麻素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有助于研究中枢神经系统相关和其他生理过程中的受体作用。最近大麻素研究的一个持续焦点是寻找新型大麻模拟化合物，这些化合物可能具有广受欢迎的治疗功能而没有明显的副作用。该项目的目标是通过在两个方面进行实验工作来识别大麻素受体的新且有效的大麻素配体。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，并测试代谢物的纯形式的受体结合活性。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，并可能具有改进的副作用。该假设得到了我们实验室最近获得的结果的支持，该结果显示了 WIN55212-2 的两种代谢物的有效 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种大麻素配体。这部分实验的结果将为两个重要问题提供答案：代谢物中保留了多少结合亲和力以及对 CB1和CB2在代谢物中保留。在第二个方面，我们寻求筛选选定的中草药成分中的大麻模拟化合物，这些成分将被提取和分离用于受体结合测定。启动这项研究的基本原理是基于结构不同的化合物（例如氨基烷基吲哚和经典大麻素）可以具有有效的受体结合活性。这意味着很可能存在不同结构和来源的其他激动剂。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先导药物。我们的策略是使用草药提取物的部分色谱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受到进一步的纯化和结构阐明，直到鉴定出负责大麻素受体结合的单个化合物。新型大麻模拟分子的发现可能为大麻素研究开辟新的场所。这种天然存在的化合物及其合成衍生物的可用性将极大地有助于我们对受体机制的理解并得出可能的治疗应用。