title: Design, Synthesis, and Characterization of Sulfamide and Sulfamate Nucleotidomimetic Inhibitors of hHint1.
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.
authors: Departments of Medicinal Chemistry and Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors: Rachit
authors: R
authors: Shah
authors: Departments of Medicinal Chemistry and Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors: Alexander
authors: A
authors: Strom
authors: Departments of Medicinal Chemistry and Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors: Andrew
authors: A
authors: Zhou
authors: Departments of Medicinal Chemistry and Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors: Kimberly M
authors: KM
authors: Maize
authors: Departments of Medicinal Chemistry and Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors: Barry C
authors: BC
authors: Finzel
authors: Departments of Medicinal Chemistry and Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors: Carston R
authors: CR
authors: Wagner
keywords: CNS; ITC; central nervous system; hHint1; human histidine triad nucleotide binding protein 1; isothermal titration calorimetry