N-(6-chloro-pyridin-3-yl)-3,4-difluoro-benzamide (ICA-27243): a novel, selective KCNQ2/Q3 potassium channel activator.
KCNQ2 (Kv7.2) and KCNQ3 (Kv7.3) are voltage-gated K(+) channel subunits that underlie the neuronal M current. In humans, mutations in these genes lead to a rare form of neonatal epilepsy (Biervert et al., 1998; Singh et al., 1998), suggesting that KCNQ2/Q3 channels may be attractive targets for novel antiepileptic drugs. In the present study, we have identified the compound N-(6-chloro-pyridin-3-yl)-3,4-difluoro-benzamide (ICA-27243) as a selective activator of the neuronal M current and KCNQ2/Q3 channels. In SH-SY5Y human neuroblastoma cells, ICA-27243 produced membrane potential hyperpolarization that could be prevented by coadministration with the M-current inhibitors 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone dihydrochloride (XE-991) and linopirdine. ICA-27243 enhanced both (86)Rb(+) efflux (EC(50) = 0.2 microM) and whole-cell currents in Chinese hamster ovary cells stably expressing heteromultimeric KCNQ2/Q3 channels (EC(50) = 0.4 microM). Activation of KCNQ2/Q3 channels was associated with a hyperpolarizing shift of the voltage dependence of channel activation (V((1/2)) shift of -19 mV at 10 microM). In contrast, ICA-27243 was less effective at activating KCNQ4 and KCNQ3/Q5 and was selective over a wide range of neurotransmitter receptors and ion channels such as voltage-dependent sodium channels and GABA-gated chloride channels. ICA-27243 (1-10 microM) was found to reversibly suppress seizure-like activity in an ex vivo hippocampal slice model of epilepsy and demonstrated in vivo anticonvulsant activity (ED(50) = 8.4 mg/kg) in the mouse maximal electroshock epilepsy model. In conclusion, ICA-27243 represents the first member of a novel chemical class of selective KCNQ2/Q3 activators with anticonvulsant-like activity in experimental models of epilepsy.
Wickenden
A D
AD
Icagen, Inc., 4222 Emperor Blvd., Durham, NC 27703, USA. jkrajewski@icagen.com
Krajewski
J L
JL
London
B
B
Wagoner
P K
PK
Wilson
W A
WA
Clark
S
S
Roeloffs
R
R
McNaughton-Smith
G
G
Rigdon
G C
GC
D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D016466:CHO Cells; D018929:Cell Culture Techniques; D002460:Cell Line; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D051658:KCNQ2 Potassium Channel / Q000187:drug effects*; D051659:KCNQ3 Potassium Channel / Q000187:drug effects*; D007668:Kidney / Q000166:cytology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008839:Microelectrodes; D009447:Neuroblastoma / Q000473:pathology; D018408:Patch-Clamp Techniques; D010957:Plasmids; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012680:Sensitivity and Specificity
D001549:Benzamides; D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; C527835:N-(6-Chloropyridin-3-yl)-3,4-difluorobenzamide; D011725:Pyridines; D012333:RNA, Messenger