Novel and High Affinity 2-[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues as Atypical Dopamine Transporter Inhibitors

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• 作者：Jianjing Cao ; Rachel D. Slack ; Oluyomi M. Bakare ; Caitlin Burzynski ; Rana Rais ; Barbara S. Slusher ; Theresa Kopajtic ; Alessandro Bonifazi ; Michael P. Ellenberger ; Hideaki Yano ; Yi He ; Guo-Hua Bi ; Zheng-Xiong Xi ; Claus J. Loland ; Amy Hauck Newman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：December 8, 2016
• 年：2016
• 卷：59
• 期：23
• 页码：10676-10691
• 全文大小：686K
• ISSN：1520-4804

文摘

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 (K_i = 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.