Open AccessDiscovery of Small Molecule Kappa Opioid Receptor Agonist and Antagonist Chemotypes through a HTS and Hit Refinement Strategy
Author(s) -
Kevin J. Frankowski,
Michael Hedrick,
Palak Gosalia,
Kelin Li,
Shenghua Shi,
David A. Whipple,
Partha Ghosh,
Thomas E. Prisinzano,
Frank J. Schoenen,
Ying Su,
Stefan Vasile,
Eduard Sergienko,
Wilson Gray,
Santosh Hariharan,
Loribelle Milan,
Susanne HeynenGenel,
Arianna Mangravita-Novo,
Michael Vicchiarelli,
Layton H. Smith,
John M. Streicher,
Marc G. Caron,
Lawrence S Barak,
Laura M. Bohn,
Thomas D.Y. Chung,
Jeffrey Aubé
Publication year - 2012
Publication title -
acs chemical neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.158
H-Index - 69
ISSN - 1948-7193
DOI - 10.1021/cn200128x
Subject(s) - chemotype , agonist , κ opioid receptor , pharmacology , kappa , antagonist , chemistry , opioid , stereochemistry , small molecule , opioid receptor , receptor , computational biology , biology , biochemistry , mathematics , chromatography , essential oil , geometry
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.