The drug abuse problem in general and the widespread use of marijuana in particular have focused attention on the chemistry and pharmacology of the plant Cannabis Sativa. In the decade since the discovery of the cannabinoid receptors, much progress has been made in the cannabinoid field. It has been established that there are at least two types of cannabinoid receptors; CB1 receptors which are present both inside and outside the central nervous system (CNS) and CB2 receptors which are found mainly in the periphery. Two main endogenous ligands have been discovered, anandamide (AEA) and 2-arachidonylglycerol (2-Ara-Gl). Also known as endocannabinoids, they are both present in central as well as peripheral tissues. Several chemically distinct and diverse structural classes of compounds which have no chemical/structural relationships have been discovered as ligands for the cannabinoid receptors. The goal of the proposed synthetic research is to generate chemical probes which will help in understanding the mechanisms involved and the role of endocannabinoids in the CNS and the periphery.
Our Specific Aims are (1) to continue the synthesis of analogs of the antagonist SR141716A and study the Antagonists 0-1269, and 0-1788 discovered in our laboratory (2) to synthesize analogs of 2-Ara-Gl and arvanil (3) to synthesize selective transporter (AMT) inhibitors (4) to prepare cannabidiol (CBD) and cannabichromene (CBC) metabolites and (5) to continue to supply AEA, 2-Ara-G] and ligands of interest to the group for further biological testing. The synthesis of these analogs will provide endocannabinoid probes for both in vitro and in vivo studies and the results could point us in the direction of other cannabinoid receptor subtypes, reveal mechanisms involved in brain function and lead to therapeutic drugs in the areas of inflammation, pain, immune response, neuroprotection in head injury and other CNS related diseases. The proposed study will help our understanding of the pharmacological action of this important class of compounds and provide drugs in the health care field.
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