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

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

来源：ACS Chemical Neuroscience, 2012, 3(3): 221-236.

DOI：10.1021/cn200128x

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

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 (kappa) opioid receptor (KOR) activation and inhibition. In this program, we have developed potent antagonists (IC50 %26lt; 120 nM) or agonists of high binding affinity (K-i %26lt; 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.

• 出版日期2012-3