1228076-12-7Relevant articles and documents
Characterization of a novel high-potency positive modulator of K v7 channels
Dalby-Brown, William,Jessen, Carsten,Hougaard, Charlotte,Jensen, Marianne L.,Jacobsen, Thomas A.,Nielsen, Karin S.,Erichsen, Helle K.,Grunnet, Morten,Ahring, Philip K.,Christophersen, Palle,Str?b?k, Dorte,J?rgensen, Susanne
, p. 52 - 63 (2013)
Kv7 channel activators decrease neuronal excitability and might potentially treat neuronal hyperexcitability disorders like epilepsy and mania. Here we introduce NS15370 ((2-(3,5-difluorophenyl)-N-[6-[(4-fluorophenyl) methylamino]-2-morpholino-3-pyridyl]acetamide)hydrochloride, an in vitro high-potency chemical analogue of retigabine, without effects on GABA A receptors. NS15370 activates recombinant homo- and heteromeric Kv7.2-Kv7.5 channels in HEK293 cells at sub-micromolar concentrations (EC50～100 nM, as quantified by a fluorescence based Tl+-influx assay). In voltage clamp experiments NS15370 exhibits a complex, concentration-dependent mode-of-action: At low concentrations it accelerates voltage-dependent activation rates, slows deactivations, and increases steady-state current amplitudes. Quantified by the peak-tail current method, the V12 value of the steady-state activation curve is shifted towards hyperpolarized potentials at concentrations ～100 times lower than retigabine. However, in contrast to retigabine, NS15370 also introduces a distinct time-dependent current decrease, which eventually, at higher concentrations, causes suppression of the current at depolarized potentials, and an apparent cross-over of the voltage-activation curve. In brain slices, NS15370 hyperpolarizes and increases spike frequency adaptation of hippocampal CA1 neurons and the compound reduces the autonomous firing of dopaminergic neurons in the substantia-nigra pars compacta. NS15370 is effective in rodent models of hyperexcitability: (i) it yields full protection against mouse 6 Hz seizures and rat amygdala kindling discharges, two models of partial epilepsia; (ii) it reduces (+)-MK-801 hydrogen maleate (MK-801)-induced hyperactivity as well as chlordiazepoxide (CDP)+d-amphetamine (AMP)-induced hyperactivity, models sensitive to classic anti-psychotic and anti-manic treatments, respectively. Our findings with NS15370 consolidate neuronal Kv7 channels as targets for anti-epileptic and psychiatric drug development.
