Design, Synthesis, and Characterization of Sulfamide and Sulfamate Nucleotidomimetic Inhibitors of hHint1

Rachit Shah, Alexander Strom, Andrew Zhou, Kimberly M. Maize, Barry C. Finzel, Carston R. Wagner

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Hint1 has recently emerged to be an important target of interest due to its involvement in the regulation of a broad range of CNS functions including opioid signaling, tolerance, neuropathic pain, and nicotine dependence. A series of inhibitors were rationally designed, synthesized, and tested for their inhibitory activity against hHint1 using isothermal titration calorimetry (ITC). The studies resulted in the development of the first small-molecule inhibitors of hHint1 with submicromolar binding affinities. A combination of thermodynamic and high-resolution X-ray crystallographic studies provides an insight into the biomolecular recognition of ligands by hHint1. These novel inhibitors have potential utility as molecular probes to better understand the role and function of hHint1 in the CNS.

Original languageEnglish (US)
Pages (from-to)780-784
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume7
Issue number8
DOIs
StatePublished - Aug 11 2016

Keywords

  • CNS
  • ITC
  • central nervous system
  • hHint1
  • human histidine triad nucleotide binding protein 1
  • isothermal titration calorimetry

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