Discovery of small molecule kappa opioid receptor agonist and antagonist chemotypes through a HTS and Hit refinement strategy

Kevin J. Frankowski, Michael P. Hedrick, Palak Gosalia, Kelin Li, Shenghua Shi, David Whipple, Partha Ghosh, Thomas E. Prisinzano, Frank J. Schoenen, Ying Su, S. Vasile, Eduard Sergienko, Wilson Gray, Santosh Hariharan, Loribelle Milan, Susanne Heynen-Genel, Arianna Mangravita-Novo, Michael Vicchiarelli, Layton H. Smith, John M. StreicherMarc G. Caron, Lawrence S. Barak, Laura M. Bohn, Thomas D.Y. Chung, Jeffrey Aubé

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Herein we present the outcome of a high throughput screening (HTS) campaign-based strategy for the rapid identification 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.

Original languageEnglish (US)
Pages (from-to)221-236
Number of pages16
JournalACS Chemical Neuroscience
Volume3
Issue number3
DOIs
StatePublished - Mar 21 2012
Externally publishedYes

Keywords

  • Kappa opioid receptor agonist
  • high-throughput screening
  • kappa opioid receptor antagonist

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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