Structure–Activity Relationship Studies on a Series of 3α-[Bis(4-fluorophenyl)methoxy]tropanes and 3α-[Bis(4-fluorophenyl)methylamino]tropanes As Novel Atypical Dopamine Transporter (DAT) Inhibitors for the Treatment of Cocaine Use Disorders

The development of medications to
treat cocaine 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 of cocaine that can lead to addiction,
atypical DAT inhibitors have been developed that prevent cocaine from
binding to DAT, but they themselves are not cocaine-like. Herein,
a series of novel DAT inhibitors were synthesized, and based on its
pharmacological profile, the lead compound 10a was evaluated
in phase I metabolic stability studies in mouse liver microsomes and
compared to cocaine in locomotor activity and drug discrimination
paradigms in mice. A molecular dynamic simulation study supported
the hypothesis that atypical DAT inhibitors have similar binding poses
at DAT in a conformation that differs from that of cocaine. Such differences
may ultimately contribute to their unique behavioral profiles and
potential for development as cocaine use disorder therapeutics.