The long-term goal of this SBIR project is to develop medications acting through the CB1cannabinoid receptor for the treatment of cocaine abuse. The cannabinergic system has been implicated in a number of neuropsychiatric conditions including drug addiction. Also, it was recently shown that the CB1 selective antagonist SR141716A, a biaryl pyrazole compound developed by Sanofi, attenuates relapse induced by re-exposure to cocaine-associated cues or cocaine itself. SR141716A is currently in clinical trials as an antiobesity medication. However, it is not being considered by Sanofi as a potential medication for cocaine and has not been made available for development for such an indication. Additionally, SR141716A has a long half-life in humans (approximately 4 days), thus, introducing uncertainties regarding its pharmacokinetic profile indifferent patients. Here we propose to develop novel CB1 antagonists with improved pharmacokinetic and pharmacodynamic profiles. The series of molecules described in this application represents novel analogs that are expected to possess higher affinities and selectivities for CB1 as well as shorter in vivo half-lives. The novel compounds will be synthesized and tested for their affinities for the CB1 and CB2 receptors as well as for their functional properties represented by their ability to activate the Gi-proteins. Computer modeling methods will be used to obtain optimization of the lead compounds, as required. In vivo testing of the most promising compounds will be carried out using the locomotor, cocaine discrimination and cocaine self administration assays with the locomotor assay being used to determine the in vivo half-lives of the compounds. Further lead optimization, if required, as well as full preclinical evaluation of a lead compound and two back-ups will be carried out under the auspices of Phase II of this project. Phase II will also include all testing required for IND submission.