Development of Neurochemical Normalization (“Agonist Substitution”) Therapeutics for Stimulant Abuse: Focus on the Dopamine Uptake Inhibitor, GBR12909

At the present time, there are no drugs are approved in the U.S. for the treatment of stimulant abuse. Based on a diverse body of preclinical data, sometimes termed the “dopamine hypothesis” of drug addiction, one approach to the treatment and prevention of stimulant abuse is the development of high affinity inhibitors of the dopamine transporter. This approach awaits clinical validation. As part of our program on the development of novel probes to study the structure and function of central nervous system, we have focused on the high affinity dopamine transport inhibitor GBR12909 (1- {2-[bis-(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine) as a tool to test the dopamine hypothesis in humans. Various analogues of GBR12909 have been evaluated both in vitro and in vivo. In particular, behavioral studies have shown that GBR12909 and several of its analogues decrease cocaine-maintained responding without affecting food-maintained responding and also appear to have reduced abuse liability as compared to cocaine in the monkey. Initial clinical studies in humans demonstrated that orally administered GBR12909 is safe, well-tolerated and achieves moderate occupancy of the dopamine transporter. This article will review the structure-activity relationships of GBR-type agents at the biogenic amine transporters, their biological activity and their potential as tools to test the dopamine hypothesis of cocaine addiction in humans.