Jianjing Cao1, Rachel D Slack1, Oluyomi M Bakare1, Caitlin Burzynski1,2, Rana Rais2, Barbara S Slusher2, Theresa Kopajtic3, Alessandro Bonifazi1, Michael P Ellenberger1, Hideaki Yano1, Yi He1, Guo-Hua Bi1, Zheng-Xiong Xi1, 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. Department of Neurology, Johns Hopkins Drug Discovery, The Johns Hopkins University School of Medicine , 855 N. Wolfe Street, Baltimore, Maryland 21205, United States. 3. Psychobiology Section, Molecular Neuropsychiatry Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health , 251 Bayview Boulevard, Baltimore, Maryland 21224, United States. 4. Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , DK-2200 Copenhagen, Denmark.
Abstract
The development of pharmacotherapeutic treatments of psychostimulant abuse has remained a challenge, despite significant efforts made toward relevant mechanistic targets, such as the dopamine transporter (DAT). The atypical DAT inhibitors have received attention due to their promising pharmacological profiles in animal models of cocaine and methamphetamine abuse. Herein, we report a series of modafinil analogues that have an atypical DAT inhibitor profile. We extended SAR by chemically manipulating the oxidation states of the sulfoxide and the amide functional groups, halogenating the phenyl rings, and/or functionalizing the terminal nitrogen with substituted piperazines, resulting in several novel leads such as 11b, which demonstrated high DAT affinity (Ki = 2.5 nM) and selectivity without producing concomitant locomotor stimulation in mice, as compared to cocaine. These results are consistent with an atypical DAT inhibitor profile and suggest that 11b may be a potential lead for development as a psychostimulant abuse medication.
The development of pharmacotherapeutic treatments of psychostimulant abuse has remained a challenge, despite significant efforts made toward relevant mechanistic targets, such as the dopamine transporter (n class="Gene">DAT). The atypical DAT inhibitors have received attention due to their promising pharmacological profiles in animal models of cocaine andmethamphetamine abuse. Herein, we report a series of modafinil analogues that have an atypical DAT inhibitor profile. We extended SAR by chemically manipulating the oxidation states of the sulfoxide and the amide functional groups, halogenating the phenyl rings, and/or functionalizing the terminal nitrogen with substituted piperazines, resulting in several novel leads such as 11b, which demonstrated high DAT affinity (Ki = 2.5 nM) and selectivity without producing concomitant locomotor stimulation in mice, as compared to cocaine. These results are consistent with an atypical DAT inhibitor profile and suggest that 11b may be a potential lead for development as a psychostimulant abuse medication.
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