The development of new medications for the treatment of marijuana and psychostimulant abuse is extremely important to the welfare of the United States. To date great advances have been made in understanding the biological and pharmacological mechanisms of illicit drugs. Approaches to the development of a pharmacotherapy have focused on the monoamine-regulated circuitry in the central nervous system. Exploration of dopaminergic and sertonergic transmission has revealed tremendous amounts of information important to understanding mechanisms of psychostimulant abuse. However, direct modulation of these neurological systems has been unsuccessful in producing sustainable therapeutic effects. In lieu of the lack of success with monoamine therapeutics, researchers have turned attention to alternative mechanisms to effect dopaminergic transmission associated with addiction. It has been suggested that the cannabinoid receptor system can indirectly modulate dopaminergic transmission and thus mediate the effects of psychostimulants on brain circuitry. To this end, it has been suggested that cannabinoid antagonists could have potential utility as medications for psychostimulant addiction in addition to cannabinoid abuse. This proposal will focus on the development of a clinically useful cannabinoid antagonist that could have application for the treatment of cannabinoid and/or psychostimulant addiction. To achieve the goal of the proposed study the specific aims are as follows: 1. Synthesize novel compounds and characterize binding affinity at cannabinoid receptors. Ligand design rationale will utilize developing SAR for each series, lead compounds in the literature and computational methods to optimize potency and lipophilicity. 2. Synthesized compounds that exhibit potent (Ki values <100 nM) receptor affinity will be evaluated in vitro functional assays to identify compounds with antagonist activity. 3. Compounds identified in Specific Aims A1-A2 that exhibit the most promising pharmacological profiles (antagonists) will be evaluated in vivo for the following:
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