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. Streicher; Marc G. Caron; Lawrence S. Barak; Laura M. Bohn; Thomas D.Y. Chung; Jeffrey Aubé

doi:10.1021/cn200128x

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 journal › Article › peer-review

46 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 language	English (US)
Pages (from-to)	221-236
Number of pages	16
Journal	ACS Chemical Neuroscience
Volume	3
Issue number	3
DOIs	https://doi.org/10.1021/cn200128x
State	Published - Mar 21 2012
Externally published	Yes

Keywords

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

ASJC Scopus subject areas

Biochemistry
Physiology
Cognitive Neuroscience
Cell Biology

Access to Document

10.1021/cn200128x

Cite this

Frankowski, K. J., Hedrick, M. P., Gosalia, P., Li, K., Shi, S., Whipple, D., Ghosh, P., Prisinzano, T. E., Schoenen, F. J., Su, Y., Vasile, S., Sergienko, E., Gray, W., Hariharan, S., Milan, L., Heynen-Genel, S., Mangravita-Novo, A., Vicchiarelli, M., Smith, L. H., ... Aubé, J. (2012). Discovery of small molecule kappa opioid receptor agonist and antagonist chemotypes through a HTS and Hit refinement strategy. ACS Chemical Neuroscience, 3(3), 221-236. https://doi.org/10.1021/cn200128x

Frankowski, 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, Chung, TDY & Aubé, J 2012, 'Discovery of small molecule kappa opioid receptor agonist and antagonist chemotypes through a HTS and Hit refinement strategy', ACS Chemical Neuroscience, vol. 3, no. 3, pp. 221-236. https://doi.org/10.1021/cn200128x

@article{874f6a8f8bca4695bce56f3264e6c147,

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

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.",

keywords = "Kappa opioid receptor agonist, high-throughput screening, kappa opioid receptor antagonist",

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

year = "2012",

month = mar,

day = "21",

doi = "10.1021/cn200128x",

language = "English (US)",

volume = "3",

pages = "221--236",

journal = "ACS Chemical Neuroscience",

issn = "1948-7193",

publisher = "American Chemical Society",

number = "3",

}

TY - JOUR

T1 - Discovery of small molecule kappa opioid receptor agonist and antagonist chemotypes through a HTS and Hit refinement strategy

AU - Frankowski, Kevin J.

AU - Hedrick, Michael P.

AU - Gosalia, Palak

AU - Li, Kelin

AU - Shi, Shenghua

AU - Whipple, David

AU - Ghosh, Partha

AU - Prisinzano, Thomas E.

AU - Schoenen, Frank J.

AU - Su, Ying

AU - Vasile, S.

AU - Sergienko, Eduard

AU - Gray, Wilson

AU - Hariharan, Santosh

AU - Milan, Loribelle

AU - Heynen-Genel, Susanne

AU - Mangravita-Novo, Arianna

AU - Vicchiarelli, Michael

AU - Smith, Layton H.

AU - Streicher, John M.

AU - Caron, Marc G.

AU - Barak, Lawrence S.

AU - Bohn, Laura M.

AU - Chung, Thomas D.Y.

AU - Aubé, Jeffrey

PY - 2012/3/21

Y1 - 2012/3/21

N2 - 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.

AB - 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.

KW - Kappa opioid receptor agonist

KW - high-throughput screening

KW - kappa opioid receptor antagonist

UR - http://www.scopus.com/inward/record.url?scp=84863393116&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863393116&partnerID=8YFLogxK

U2 - 10.1021/cn200128x

DO - 10.1021/cn200128x

M3 - Article

AN - SCOPUS:84863393116

SN - 1948-7193

VL - 3

SP - 221

EP - 236

JO - ACS Chemical Neuroscience

JF - ACS Chemical Neuroscience

IS - 3

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this