Arizona Health Sciences

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

TitleDiscovery of Small Molecule Kappa Opioid Receptor Agonist and Antagonist Chemotypes through a HTS and Hit Refinement Strategy.
Publication TypeJournal Article
Year of Publication2012
AuthorsFrankowski KJ, Hedrick MP, Gosalia P, Li K, Shi S, Whipple D, Ghosh P, Prisinzano TE, Schoenen FJ, Su Y, Vasile S, Sergienko E, Gray W, Hariharan S, Milan L, Heynen-Genel S, Mangravita-Novo A, Vicchiarelli M, Smith LH, Streicher JM, Caron MG, Barak LS, Bohn LM, D Y Chung T, Aubé J
JournalACS Chem Neurosci
Volume3
Issue3
Pagination221-236
Date Published2012 Mar 21
ISSN1948-7193
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.

DOI10.1021/cn200128x
Alternate JournalACS Chem Neurosci
PubMed ID22737280
PubMed Central IDPMC3378255
Grant ListU54 HG005033 / HG / NHGRI NIH HHS / United States
U01 DA022950 / DA / NIDA NIH HHS / United States
U54 HG005033-01 / HG / NHGRI NIH HHS / United States
U54 HG005031-02 / HG / NHGRI NIH HHS / United States
R01 DA031927 / DA / NIDA NIH HHS / United States
U54 HG005031 / HG / NHGRI NIH HHS / United States
R01 DA031927-01 / DA / NIDA NIH HHS / United States
U01 DA022950-01 / DA / NIDA NIH HHS / United States
Faculty Member Reference: 
John M. Streicher, PhD