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.

R03DA017141

2004-09-15

2007-07-31