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Novel KCNQ2/Q3 agonists as potential therapeutics for epilepsy and neuropathic pain.

Abstract：

: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 1 as well as their in vivo activity in animal models of epilepsy and neuropathic pain.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Fritch PC,McNaughton-Smith G,Amato GS,Burns JF,Eargle CW,Roeloffs R,Harrison W,Jones L,Wickenden AD

doi

10.1021/jm901497b

subject

Has Abstract

pub_date

2010-01-28 00:00:00

pages

887-96

issue

2

eissn

0022-2623

issn

1520-4804

journal_volume

53

pub_type

杂志文章

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