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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)10676-10691
Number of pages16
JournalJournal of medicinal chemistry
Volume59
Issue number23
DOIs
StatePublished - Dec 8 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Fingerprint Dive into the research topics of 'Novel and High Affinity 2-[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues as Atypical Dopamine Transporter Inhibitors'. Together they form a unique fingerprint.

  • Cite this

    Cao, J., Slack, R. D., Bakare, O. M., Burzynski, C., Rais, R., Slusher, B. S., Kopajtic, T., Bonifazi, A., Ellenberger, M. P., Yano, H., He, Y., Bi, G. H., Xi, Z. X., Loland, C. J., & Newman, A. H. (2016). Novel and High Affinity 2-[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues as Atypical Dopamine Transporter Inhibitors. Journal of medicinal chemistry, 59(23), 10676-10691. https://doi.org/10.1021/acs.jmedchem.6b01373