The overall and specific goal of this application is the identification of novel high affinity andselective functional agonists of the nociceptin receptor that can be used to treat cocaineaddiction. In previous efforts, we have identified, designed and synthesized novel, potent, andselective nociceptin receptor (a.k.a. ORL-1, NOP) agonists as tools for research on substancedependence with potential as clinically effective therapeutic agents. The disease target, cocaineabuse, represents an enormous health burden on society and for which currently availablepharmacotherapies have insufficient efficacy. We propose nociceptin receptor agonism as amechanism to achieve the therapeutic objective. Studies suggest that nociceptin activationopposes the dependence effects of substances of abuse such as nicotine, alcohol and cocaine.We propose nociceptin receptor activation as a mechanism to achieve the therapeutic objectiveof reduced cocaine addiction. While no clinical validation exists for the mechanism, thehypothesis supported by preclinical data, and would benefit from directed studies usingoptimized ligands, such as those we propose, to uncover the contributions of the nociceptinreceptor to cocaine abuse as the first steps in developing novel therapeutics. In this application,we extend this molecule development program to center on the design, synthesis andevaluation of agents for that can be used in cocaine addiction research with potential to becometherapeutics based on their actions at the nociceptin receptor. The pharmacology of novelcompounds will be assessed in multiple cell-based assays and will include opioid receptorcounterscreens to routinely determine potency and selectivity at a very early stage. Thecompound starting points for this project show no addictive potential, and a high level ofselectivity over the mu opioid receptor, an improvement over currentiy available NOP agonists.This application is aimed at the development of the idea that nociceptin receptor agonists canbe used to treat cocaine abuse.
Cocaine use represents an enormous worldwide health burden, in the US alone in 2009 more than 4.8million people abused cocaine. Current cocaine use therapies are simply not effective and novel therapeuticsare greatly needed. This project will test the hypothesis that the nociceptin receptor is involved in cocainereward pathways in an attempt to validate the nociceptin receptor as a target for novel therapeutics to treatcocaine abuse.
