Discovery of Drugs to Treat Cocaine Dependence: Behavioral and Neurochemical Effects of Atypical Dopamine Transport Inhibitors

Abstract

Stimulant drugs acting at the dopamine transporter (DAT), like cocaine, are widely abused, yet effective medical treatments for this abuse have not been found. Analogs of benztropine (BZT) that, like cocaine, act at the DAT have effects that differ from cocaine and in some situations block the behavioral, neurochemical, and reinforcing actions of cocaine. Neurochemical studies of dopamine levels in brain and behavioral studies have demonstrated that BZT analogs have a relatively slow onset and reduced maximal effects compared to cocaine. Pharmacokinetic studies, however, indicated that the BZT analogs rapidly access the brain at concentrations above their in vitro binding affinities, while binding in vivo demonstrates apparent association rates for BZT analogs lower than that for cocaine. Additionally, the off-target effects of these compounds do not fully explain their differences from cocaine. Initial structure-activity studies indicated that BZT analogs bind to DAT differently from cocaine and these differences have been supported by site-directed mutagenesis studies of the DAT. In addition, BZT analog-mediated inhibition of uptake was more resistant to mutations producing inward conformational DAT changes than cocaine analogs. The BZT analogs have provided new insights into the relation between the molecular and behavioral actions of cocaine and the diversity of effects produced by dopamine transport inhibitors. Novel interactions of BZT analogs with the DAT suggest that these drugs may have a pharmacology that would be useful in their development as treatments for cocaine abuse.

Preclinical Efficacy of N-Substituted Benztropine Analogs as Antagonists of Methamphetamine Self-Administration in Rats

“…Several mechanisms have been suggested for the antagonism by BZT analogs of the effects of cocaine (Hiranita et al, 2009;Tanda et al, 2009a). Previous studies examined the potential role of muscarinic or histaminic antagonist effects, though studies conducted to date provide little evidence that those actions can account for the antagonism of cocaine (Tanda et al, 2009b), and presumably that of d-methamphetamine. Nonetheless, specific binding of radiolabeled JHW007 has shown that it binds to sites other than the DAT, and that binding is not fully displaceable by M 1 or H 1 ligands, indicating still other sites as potentially contributing to the antagonist effects of BZT analogs (Kopajtic et al, 2010).…”

Lorcaserin Reduces the Discriminative Stimulus and Reinforcing Effects of Cocaine in Rhesus Monkeys

“…Worldwide estimates put the number of regular cocaine users at nearly 20 million (United Nations Office on Drugs and Crime, 2014). Despite longstanding efforts to develop pharmacotherapies (Mello, 1990;Roberts and Brebner, 2000;Platt et al, 2002;Dackis and O'Brien, 2003;Grabowski et al, 2004;Vocci et al, 2005;Tanda et al, 2009), there are currently no approved medications for treating cocaine abuse.…”

Novel N-1,2-Dihydroxypropyl Analogs of Lobelane Inhibit Vesicular Monoamine Transporter-2 Function and Methamphetamine-Evoked Dopamine Release

“…Specifically, methamphetamine reverses DA translocation by DAT to increase extracellular DA concentrations leading to reward (Fischer and Cho, 1979;Liang and Rutledge, 1982;Wise and Bozarth, 1987;Di Chiara and Imperato, 1988). Numerous studies have focused on DAT as a therapeutic target for the development of treatments for psychostimulant abuse (Grabowski et al, 1997;Dar et al, 2005;Howell et al, 2007;Tanda et al, 2009). However, this approach to drug discovery has thus far not resulted in viable efficacious therapeutics for methamphetamine abuse.…”