Novel KCNQ2/Q3 Agonists as Potential Therapeutics for Epilepsy and Neuropathic Pain

被引：47

作者：

Fritch, Paul C. ^{[1
]}

McNaughton-Smith, Grant ^{[1
]}

Amato, George S. ^{[1
]}

Burns, James F. ^{[1
]}

Eargle, C. Wesley ^{[1
]}

Roeloffs, Rosemarie ^{[1
]}

Harrison, William ^{[1
]}

Jones, Leslie ^{[1
]}

Wickenden, Alan D. ^{[1
]}

机构：

[1] Icagen Inc, Durham, NC 27703 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 02期

关键词：

POTASSIUM CHANNEL GENE; SUBSTITUTION REACTIONS; CYANINE DYES; ANTICONVULSANT; RETIGABINE; MODELS; NEUROBIOLOGY; STRATEGIES; MUTATION; CURRENTS;

D O I：

10.1021/jm901497b

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

Current drugs for the treatment of seizure disorders, although effective in many patients, still suffer from a number of failures and are not effective in some forms of resistant epilepsies. Historically, many of these drugs have multiple mechanisms of action including calcium and sodium channel blockade as well as GABAergic activity and thus a number of associated side effects. Modulation of the M-current through opening of KCNQ channels has been proposed as a way to attenuate neuroexcitability and have a therapeutic benefit for the treatment Of seizure disorders. Therefore, as part Of our program to identify new treatments for epilepsy, we set out to identify agonists of KCNQ channels. High throughput screening of our corporate collection led to the identification of 1, adamantane-1-carboxylic acid (3-methyl-3H-benzothiazol-2-ylidine) hydrazide, a potent KCNQ2/Q3 agonist. Herein, we describe the syntheses and structure-activity relationships of analogues of I its well as their in vivo activity in animal models of epilepsy and neuropathic pain.

引用

页码：887 / 896

页数：10

共 37 条

[1]

A potassium channel mutation in neonatal human epilepsy [J].