Discovery, synthesis, and structure-activity relationship of a series of N -aryl-bicyclo[2.2.1]heptane-2-carboxamides

Characterization of ML213 as a novel KCNQ2 and KCNQ4 potassium channel opener

Haibo Yu, Meng Wu, Steven D. Townsend, Beiyan Zou, Shunyou Long, J. Scott Daniels, Owen B. McManus, Min Li, Craig W. Lindsley, Corey R Hopkins

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Herein we report the discovery, synthesis, and evaluation of a series of N-aryl-bicyclo[2.2.1]heptane-2-carboxamides as selective KCNQ2 (K v7.2) and KCNQ4 (K v7.4) channel openers. The best compound, 1 (ML213), has an EC 50 of 230 nM (KCNQ2) and 510 nM (KCNQ4) and is selective for KCNQ2 and KCNQ4 channels versus a large battery of related potassium channels, as well as affording modest brain levels. This represents the first report of unique selectivity profiles for KCNQ2 and KCNQ4 over the other channels (KCNQ1/3/5) and as such should prove to be a valuable tool compound for understanding these channels in regulating neuronal activity.

Original languageEnglish (US)
Pages (from-to)572-577
Number of pages6
JournalACS Chemical Neuroscience
Volume2
Issue number10
DOIs
StatePublished - Oct 19 2011

Fingerprint

KCNQ2 Potassium Channel
Potassium Channels
Structure-Activity Relationship
Brain
N-mesitybicyclo(2.2.1)heptane-2-carboxamide
bicyclo(2.2.1)heptene

Keywords

  • KCNQ2
  • KCNQ4
  • Kv7
  • ML218
  • MLPCN probe
  • activator
  • ion channels

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

Cite this

Discovery, synthesis, and structure-activity relationship of a series of N -aryl-bicyclo[2.2.1]heptane-2-carboxamides : Characterization of ML213 as a novel KCNQ2 and KCNQ4 potassium channel opener. / Yu, Haibo; Wu, Meng; Townsend, Steven D.; Zou, Beiyan; Long, Shunyou; Daniels, J. Scott; McManus, Owen B.; Li, Min; Lindsley, Craig W.; Hopkins, Corey R.

In: ACS Chemical Neuroscience, Vol. 2, No. 10, 19.10.2011, p. 572-577.

Research output: Contribution to journalArticle

Yu, Haibo ; Wu, Meng ; Townsend, Steven D. ; Zou, Beiyan ; Long, Shunyou ; Daniels, J. Scott ; McManus, Owen B. ; Li, Min ; Lindsley, Craig W. ; Hopkins, Corey R. / Discovery, synthesis, and structure-activity relationship of a series of N -aryl-bicyclo[2.2.1]heptane-2-carboxamides : Characterization of ML213 as a novel KCNQ2 and KCNQ4 potassium channel opener. In: ACS Chemical Neuroscience. 2011 ; Vol. 2, No. 10. pp. 572-577.
@article{5b61ead7710d4db993fd5fe24ad92a27,
title = "Discovery, synthesis, and structure-activity relationship of a series of N -aryl-bicyclo[2.2.1]heptane-2-carboxamides: Characterization of ML213 as a novel KCNQ2 and KCNQ4 potassium channel opener",
abstract = "Herein we report the discovery, synthesis, and evaluation of a series of N-aryl-bicyclo[2.2.1]heptane-2-carboxamides as selective KCNQ2 (K v7.2) and KCNQ4 (K v7.4) channel openers. The best compound, 1 (ML213), has an EC 50 of 230 nM (KCNQ2) and 510 nM (KCNQ4) and is selective for KCNQ2 and KCNQ4 channels versus a large battery of related potassium channels, as well as affording modest brain levels. This represents the first report of unique selectivity profiles for KCNQ2 and KCNQ4 over the other channels (KCNQ1/3/5) and as such should prove to be a valuable tool compound for understanding these channels in regulating neuronal activity.",
keywords = "KCNQ2, KCNQ4, Kv7, ML218, MLPCN probe, activator, ion channels",
author = "Haibo Yu and Meng Wu and Townsend, {Steven D.} and Beiyan Zou and Shunyou Long and Daniels, {J. Scott} and McManus, {Owen B.} and Min Li and Lindsley, {Craig W.} and Hopkins, {Corey R}",
year = "2011",
month = "10",
day = "19",
doi = "10.1021/cn200065b",
language = "English (US)",
volume = "2",
pages = "572--577",
journal = "ACS Chemical Neuroscience",
issn = "1948-7193",
publisher = "American Chemical Society",
number = "10",

}

TY - JOUR

T1 - Discovery, synthesis, and structure-activity relationship of a series of N -aryl-bicyclo[2.2.1]heptane-2-carboxamides

T2 - Characterization of ML213 as a novel KCNQ2 and KCNQ4 potassium channel opener

AU - Yu, Haibo

AU - Wu, Meng

AU - Townsend, Steven D.

AU - Zou, Beiyan

AU - Long, Shunyou

AU - Daniels, J. Scott

AU - McManus, Owen B.

AU - Li, Min

AU - Lindsley, Craig W.

AU - Hopkins, Corey R

PY - 2011/10/19

Y1 - 2011/10/19

N2 - Herein we report the discovery, synthesis, and evaluation of a series of N-aryl-bicyclo[2.2.1]heptane-2-carboxamides as selective KCNQ2 (K v7.2) and KCNQ4 (K v7.4) channel openers. The best compound, 1 (ML213), has an EC 50 of 230 nM (KCNQ2) and 510 nM (KCNQ4) and is selective for KCNQ2 and KCNQ4 channels versus a large battery of related potassium channels, as well as affording modest brain levels. This represents the first report of unique selectivity profiles for KCNQ2 and KCNQ4 over the other channels (KCNQ1/3/5) and as such should prove to be a valuable tool compound for understanding these channels in regulating neuronal activity.

AB - Herein we report the discovery, synthesis, and evaluation of a series of N-aryl-bicyclo[2.2.1]heptane-2-carboxamides as selective KCNQ2 (K v7.2) and KCNQ4 (K v7.4) channel openers. The best compound, 1 (ML213), has an EC 50 of 230 nM (KCNQ2) and 510 nM (KCNQ4) and is selective for KCNQ2 and KCNQ4 channels versus a large battery of related potassium channels, as well as affording modest brain levels. This represents the first report of unique selectivity profiles for KCNQ2 and KCNQ4 over the other channels (KCNQ1/3/5) and as such should prove to be a valuable tool compound for understanding these channels in regulating neuronal activity.

KW - KCNQ2

KW - KCNQ4

KW - Kv7

KW - ML218

KW - MLPCN probe

KW - activator

KW - ion channels

UR - http://www.scopus.com/inward/record.url?scp=80054878125&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80054878125&partnerID=8YFLogxK

U2 - 10.1021/cn200065b

DO - 10.1021/cn200065b

M3 - Article

VL - 2

SP - 572

EP - 577

JO - ACS Chemical Neuroscience

JF - ACS Chemical Neuroscience

SN - 1948-7193

IS - 10

ER -