Mu-Fa Zou1, Jianjing Cao1, Ara M Abramyan1, Theresa Kopajtic2, Claudio Zanettini1, Daryl A Guthrie1, Rana Rais3, Barbara S Slusher3, Lei Shi1, Claus J Loland4, Amy Hauck Newman1. 1. Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States. 2. Psychobiology Section, Molecular Neuropsychiatry Research Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 251 Bayview Boulevard, Baltimore, Maryland 21224, United States. 3. Department of Neurology, Johns Hopkins Drug Discovery, The Johns Hopkins University School of Medicine , 855 North Wolfe Street, Baltimore, Maryland 21205, United States. 4. Molecular Faculty of Health and Medical Sciences, University of Copenhagen , DK-2200 Copenhagen, Denmark.
Abstract
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.
The development of medications to treat n class="Chemical">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.
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