The Medications Development Branch of NIDA has identified administration of dopamine agonist compounds as one of the leading current approaches to the pharmacotherapy of cocaine abuse. The pharmacological rationale for this treatment is to compensate for the diminished synaptic dopaminergic tone in the absence of cocaine. The striatal region of the brain, which is implicated in the reward reinforcement pathway of cocaine, is also the primary site of D3 dopaminergic postsynaptic neurons. Thus a D3 selective agonist drug is proposed as a potential treatment agent to mitigate cocaine craving during withdrawal. The proposal describes our approach to the rational design of novel D3 selective ligand compounds, which utilize a novel structural feature to enhance ligand binding potency.The laboratory implementation of this project employs a "combinatorial" synthesis scheme to prepare a matrix of compounds, which embody systematic structural variation. The result of this scheme is a modest advantage in the synthetic and pharmacological testing effort. We will concentrate on the combinatorial synthesis of nine compounds; the identification of the most potent D3 compound, and full characterization of this compound's pharmacological profile and agonist efficacy. Ultimately, the intention is to develop a commercial viable medication to treat cocaine abuse in humans.Proposed commercial application:Successful development of a potent D3 selective dopaminergic agonist compound, with further optimization of bioavailability and toxicological properties, could provide a new therapeutic drug for the alleviation of drug craving amongst cocaine users undergoing treatment. Sales of such a therapeutic compound could amount to $200 to $300 million per year in the US.National Institute on Drug Abuse (NIDA)
