Novel KCNQ2/Q3 agonists as potential therapeutics for epilepsy and neuropathic pain.
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.
Fritch
Paul C
PC
Icagen, Inc., Suite 390, 4222 Emperor Boulevard, Durham, North Carolina 27703, USA. pfritch@icagen.com
McNaughton-Smith
Grant
G
Amato
George S
GS
Burns
James F
JF
Eargle
C Wesley
CW
Roeloffs
Rosemarie
R
Harrison
William
W
Jones
Leslie
L
Wickenden
Alan D
AD
D000218:Adamantane / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001386:Azides / Q000737:chemistry / Q000494:pharmacology; D004827:Epilepsy / Q000188:drug therapy*; D051658:KCNQ2 Potassium Channel / Q000819:agonists*; D051659:KCNQ3 Potassium Channel / Q000819:agonists*; D051379:Mice; D009437:Neuralgia / Q000188:drug therapy*; D013329:Structure-Activity Relationship
D001386:Azides; D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; D000218:Adamantane