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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.
This article was published in the following journal.
Name: Journal of medicinal chemistry
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A quantitative prediction of the biological, ecotoxicological or pharmaceutical activity of a molecule. It is based upon structure and activity information gathered from a series of similar compounds.
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A spectroscopic technique which uses the Mossbauer effect (inelastic scattering of gamma radiation resulting from interaction with heavy nuclei) to monitor the small variations in the interaction between an atomic nucleus and its environment. Such variations may be induced by changes in temperature, pressure, chemical state, molecular conformation, molecular interaction, or physical site. It is particularly useful for studies of structure-activity relationship in metalloproteins, mobility of heavy metals, and the state of whole tissue and cell membranes.
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