The development of medications to treat cocaine or methamphetamine use disorders has thus far defied success, leaving this patient population without pharmacotherapeutic options.  As the dopamine transporter (DAT) plays a prominent role in the reinforcing effects that can lead to addiction of these abused psychostimulants, atypical DAT inhibitors have been developed that are not cocaine- or methamphetamine-like, behaviorally.  Over the past 25 years, we have synthesized series of novel DAT inhibitors based on benztropine, rimcazole and modafinil and extended SAR by chemically modifying and hybridizing these parent molecules. Molecular pharmacology and molecular dynamic simulation studies support the hypothesis that these dopamine uptake inhibitors have similar binding poses to one another, but bind in a conformation that differs from that of cocaine. In general, these compounds do not 1) produce locomotor stimulation, 2) generalize to the cocaine discriminative stimulus nor are they self administered in rodents, in contrast to cocaine or methamphetamine.  Moreover, several of our lead compounds attenuate behaviors produced in these animal models, by these illicit drugs, supporting their development for the treatment of psychostimulant use disorders.<br/>

Novel and atypical DAT inhibitors for the treatment of psychostimulant use disorders

255th National Meeting (2018)

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