RECEPTOR BINDING PROPERTIES OF CANNABINOID METABOLITES

描述（由申请人提供）：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类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所寻求的治疗功能，而没有显著的副作用。本项目的目标是阐明三种结构不同的洋杉碱类化合物的体外生物转化途径，并评估其主要代谢产物的受体结合活性。我们假设大麻素激动剂/拮抗剂的某些代谢产物可能保留受体结合特性，并可能具有经修改的副作用，这些副作用可以通过体内测定进一步评估。我们实验室最近获得的结果支持了这一假设，这些结果显示了WIN 55212 -2的两种代谢物对CB 1和CB 2的强效结合能力。为了进一步验证这一假设，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最近发现的三种大麻素配体。尚未研究这些配体的代谢途径，代谢物的结合特性（如果有的话）也未知。因此，这项研究的意义是双重的。首先，对最近开发的大麻素受体配体的代谢研究将为其生物转化途径提供新的知识。其次，来自对分离的代谢物的受体结合测定的结果将提供两个重要问题的答案：1）代谢物中保留了多少结合亲和力和2）代谢物中保留了多少对CBI和CB 2的选择性。

DESCRIPTION (provided by applicant): 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 eannabinoid 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 elucidate in vitro biotransformation pathways of three structurally distinct eannabinoid compounds and to evaluate the receptor binding activities of their major metabolites. We hypothesize that certain metabolic products of cannabinoid agonists/antagonists may retain receptor-binding properties and have possible modified side effects that can be further evaluated by in vivo assays. This hypothesis is supported by recent results obtained in our laboratory that show potent CB1 and CB2 binding ability for two metabolites of WIN55212-2. To further test the hypothesis we propose to extend the study of metabolism and receptor binding activities of metabolites to three recently found cannabinoid ligands. The metabolic pathways of these ligands have not been studied and the binding properties of the metabolites, if any, are unknown. The significance of this research is therefore two fold. First, metabolism study of the most recently developed ligands for cannabinoid receptors will provide new knowledge on their biotransformation pathways. Second, results from the receptor binding assays on the isolated metabolites will provide answers to two important questions: 1) how much binding affinity is retained in the metabolites and 2) how much selectivity for CBI and CB2 is reserved in the metabolites.