CANNABINOID RECEPTOR LIGANDS--SAR

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Delta9-Tetrahydrocannabinol (THC) is the primary CNS-active component of marijuana or hashish (Cannabis sativa). Potent tricyclic and bicyclic cannabinoid analogs developed at Pfizer Central Research were utilized to elucidate a cellular mechanism of action for delta9-THC. We determined that cannabimimetic compounds interact with a cannabinoid receptor on neuronal cells which regulates the cyclic AMP second messenger system. We developed a radioligand binding assay using the potent bicyclic cannabinoid agonist [3H]CP-55940, and have used it to biochemically and pharmacologically characterize the cannabinoid receptor. The goal of this project is to study cannabinoid receptor-ligand interactions at the cellular and molecular levels. This work will continue through the following specific aims to: 1.Continue characterization of novel affinity ligands and positron emission tomography (PET) scanning ligands; 2.Identify a cannabinoid-like binding activity present in the CNS, and characterize and purify the factor(s) responsible for this activity; and 3.Develop an immunoassay for the cannabinoid-like binding factor(s). It is expected that the determination and characterization of an endogenous cannabinoid-like binding factor(s) for the cannabinoid receptor will allow the development of new structure-activity relationship studies based on this novel molecule. This knowledge could lead to the development of potentially useful antagonists for the cannabinoid receptor. In addition, receptor subtypes for the endogenous cannabinoid-like binding factor could be sought. These studies will advance our understanding of the role of cannabinoceptive neurons in analgesia, cognition and memory, and motor behaviors.