Discovery of Small Molecule Kappa Opioid Receptor Agonist and Antagonist Chemotypes through a HTS and Hit Refinement Strategy.
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.
University of Kansas Specialized Chemistry Center, University of Kansas, Lawrence, KS 66047.
Kevin J
KJ
Frankowski
Michael P
MP
Hedrick
Palak
P
Gosalia
Kelin
K
Li
Shenghua
S
Shi
David
D
Whipple
Partha
P
Ghosh
Thomas E
TE
Prisinzano
Frank J
FJ
Schoenen
Ying
Y
Su
S
S
Vasile
Eduard
E
Sergienko
Wilson
W
Gray
Santosh
S
Hariharan
Loribelle
L
Milan
Susanne
S
Heynen-Genel
Arianna
A
Mangravita-Novo
Michael
M
Vicchiarelli
Layton H
LH
Smith
John M
JM
Streicher
Marc G
MG
Caron
Lawrence S
LS
Barak
Laura M
LM
Bohn
Thomas D Y
TD
Chung
Jeffrey
J
Aubé