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.
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