The new KCNQ2 activator 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid displays anticonvulsant potential

Boehlen A, Schwake M, Dost R, Kunert A, Fidzinski P, Heinemann U, Gebhardt C (2013)
British Journal of Pharmacology 168(5): 1182-1200.

Zeitschriftenaufsatz | Veröffentlicht | Englisch
 
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Autor*in
Boehlen, A; Schwake, MichaelUniBi ; Dost, R; Kunert, A; Fidzinski, P; Heinemann, U; Gebhardt, C
Alternativer Titel
M-current-mediated neuronal modulation
Abstract / Bemerkung
Background and Purpose:
KCNQ2-5 channels are voltage-gated potassium channels that regulate neuronal excitability and represent suitable targets for the treatment of hyperexcitability disorders. The effect of Chlor-N-(6-chlor-pyridin-3-yl)-benzamid was tested on KCNQ subtypes for its ability to alter neuronal excitability and for its anticonvulsant potential.
Experimental Approach:
The effect of 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid was evaluated using whole-cell voltage-clamp recordings from CHO cells and Xenopus laevis oocytes expressing different types of KCNQ channels. Epileptiform afterdischarges were recorded in fully amygdala-kindled rats in vivo. Neuronal excitability was assessed using field potential and whole cell recording in rat hippocampus in vitro.
Key Results:
4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid caused a hyperpolarizing shift of the activation curve and a pronounced slowing of deactivation in KCNQ2-mediated currents, whereas KCNQ3/5 heteromers remained unaffected. The effect was also apparent in the Retigabine-insensitive mutant KCNQ2-W236L. In fully amygdala-kindled rats, it elevated the threshold for induction of afterdischarges and reduced seizure severity and duration. In hippocampal CA1 cells, 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid strongly damped neuronal excitability caused by a membrane hyperpolarization and a decrease in membrane resistance and induced an increase of the somatic resonance frequency on the single cell level, whereas synaptic transmission was unaffected. On the network level, 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid caused a significant reduction of γ and θ oscillation peak power, with no significant change in oscillation frequency.
Conclusion and Implications:
Our data indicate that 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid is a potent KCNQ activator with a selectivity for KCNQ2 containing channels. It strongly reduces neuronal excitability and displays anticonvulsant activity in vivo.
Erscheinungsjahr
2013
Zeitschriftentitel
British Journal of Pharmacology
Band
168
Ausgabe
5
Seite(n)
1182-1200
ISSN
0007-1188
Page URI
https://pub.uni-bielefeld.de/record/2953339

Zitieren

Boehlen A, Schwake M, Dost R, et al. The new KCNQ2 activator 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid displays anticonvulsant potential. British Journal of Pharmacology. 2013;168(5):1182-1200.
Boehlen, A., Schwake, M., Dost, R., Kunert, A., Fidzinski, P., Heinemann, U., & Gebhardt, C. (2013). The new KCNQ2 activator 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid displays anticonvulsant potential. British Journal of Pharmacology, 168(5), 1182-1200. https://doi.org/10.1111/bph.12065
Boehlen, A., Schwake, M., Dost, R., Kunert, A., Fidzinski, P., Heinemann, U., and Gebhardt, C. (2013). The new KCNQ2 activator 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid displays anticonvulsant potential. British Journal of Pharmacology 168, 1182-1200.
Boehlen, A., et al., 2013. The new KCNQ2 activator 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid displays anticonvulsant potential. British Journal of Pharmacology, 168(5), p 1182-1200.
A. Boehlen, et al., “The new KCNQ2 activator 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid displays anticonvulsant potential”, British Journal of Pharmacology, vol. 168, 2013, pp. 1182-1200.
Boehlen, A., Schwake, M., Dost, R., Kunert, A., Fidzinski, P., Heinemann, U., Gebhardt, C.: The new KCNQ2 activator 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid displays anticonvulsant potential. British Journal of Pharmacology. 168, 1182-1200 (2013).
Boehlen, A, Schwake, Michael, Dost, R, Kunert, A, Fidzinski, P, Heinemann, U, and Gebhardt, C. “The new KCNQ2 activator 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid displays anticonvulsant potential”. British Journal of Pharmacology 168.5 (2013): 1182-1200.
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