Discovery of Small Molecule Kappa Opioid Receptor Agonist and Antagonist Chemotypes through a HTS and Hit Refinement Strategy

University of Kansas Specialized Chemistry Center, University of Kansas, Lawrence, KS 66047.
ACS Chemical Neuroscience (Impact Factor: 4.36). 01/2012; 3(3). DOI: 10.1021/cn200128x


Herein we present the outcome of a high throughput screening (HTS) campaign-based strategy for the rapid identifica-tion and optimization of selective and general chemotypes for both kappa (κ) opioid receptor (KOR) activation and inhibition. In this program, we have developed potent antagonists (IC 50 < 120 nM) or agonists of high binding affinity (K i < 3 nM). In contrast to many important KOR ligands, the compounds presented here are highly modular, readily synthesized, and, in most cases, achiral. The four new chemotypes hold promise for further development into chemical tools for studying the KOR or as potential therapeutic lead candidates. KEYWORDS: Kappa opioid receptor agonist, kappa opioid receptor antagonist, high-throughput screening T he kappa (κ) opioid receptor (KOR) regulates a wide

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