(<i>S</i>)-<i>N</i>-[1-(3-Morpholin-4-ylphenyl)ethyl]- 3-phenylacrylamide:  An Orally Bioavailable KCNQ2 Opener with Significant Activity in a Cortical Spreading Depression Model of Migraine

Wu, Yong‐Jin; Boissard, Christopher G.; Greco, Corinne; Gribkoff, Valentin K.; Harden, David G.; He, Huan; L’Heureux, Alexandre; Kang, Shing Hong; Kinney, Gene G.; Knox, Ronald J.; Natale, Joanne; Newton, Amy; Lehtinen-Oboma, Sanna; Sinz, Michael; Sivarao, Digavalli V.; Starrett, John E.; Sun, Li‐Qiang; Tertyshnikova, Svetlana; Thompson, Mark; Weaver, David T.; Wong, Henry; Zhang, Lei; Dworetzky, Steven I.

doi:10.1021/jm034073f

Cited by 58 publications

(46 citation statements)

References 19 publications

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“…There are also some similarities between the properties exhibited by meclofenamate or diclofenac and those displayed by the recently characterized KCNQ2 channel openers, acrylamide derivatives (Wu et al, 2004). Like with retigabine and fenamate compounds, the acrylamide drugs shift leftward the voltage dependence of channel activation, slow down deactivation kinetics, hyperpolarize the resting membrane potential, and produce at depolarized potentials a crossover of the current-voltage relations (Wu et al, 2003(Wu et al, , 2004. It is not clear, however, whether all these compounds act by the same mechanisms and bind to the same channel site.…”

Section: Discussionmentioning

confidence: 82%

Meclofenamic Acid and Diclofenac, Novel Templates of KCNQ2/Q3 Potassium Channel Openers, Depress Cortical Neuron Activity and Exhibit Anticonvulsant Properties

Peretz

Degani²,

Nachman³

et al. 2004

Mol Pharmacol

190

175

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The voltage-dependent M-type potassium current (M-current) plays a major role in controlling brain excitability by stabilizing the membrane potential and acting as a brake for neuronal firing. The KCNQ2/Q3 heteromeric channel complex was identified as the molecular correlate of the M-current. Furthermore, the KCNQ2 and KCNQ3 channel ␣ subunits are mutated in families with benign familial neonatal convulsions, a neonatal form of epilepsy. Enhancement of KCNQ2/Q3 potassium currents may provide an important target for antiepileptic drug development. Here, we show that meclofenamic acid (meclofenamate) and diclofenac, two related molecules previously used as anti-inflammatory drugs, act as novel KCNQ2/Q3 channel openers. Extracellular application of meclofenamate (EC 50 ϭ 25 M) and diclofenac (EC 50 ϭ 2.6 M) resulted in the activation of KCNQ2/Q3 K ϩ currents, heterologously expressed in Chinese hamster ovary cells. Both openers activated KCNQ2/Q3 channels by causing a hyperpolarizing shift of the voltage activation curve (Ϫ23 and Ϫ15 mV, respectively) and by markedly slowing the deactivation kinetics. The effects of the drugs were stronger on KCNQ2 than on KCNQ3 channel ␣ subunits. In contrast, they did not enhance KCNQ1 K ϩ currents. Both openers increased KCNQ2/Q3 current amplitude at physiologically relevant potentials and led to hyperpolarization of the resting membrane potential. In cultured cortical neurons, meclofenamate and diclofenac enhanced the M-current and reduced evoked and spontaneous action potentials, whereas in vivo diclofenac exhibited an anticonvulsant activity (ED 50 ϭ 43 mg/kg). These compounds potentially constitute novel drug templates for the treatment of neuronal hyperexcitability including epilepsy, migraine, or neuropathic pain.Voltage-dependent K ϩ (Kv) channels play a major role in brain excitability through the regulation of action potential generation and propagation, the tuning of neuronal firing patterns, or the modulation of neurotransmitter release. The M-type K ϩ channel generates a subthreshold, voltage-gated K ϩ current (M-current) that plays an important role in controlling neuronal excitability. Brown and Adams (1980) first identified the M-current in frog sympathetic neurons as a slowly activating, noninactivating, voltage-sensitive K ϩ current, which was inhibited by muscarinic acetylcholine receptor stimulation (Brown and Adams, 1980). M-currents were also characterized in hippocampal and cortical neurons (Brown, 1988;Marrion, 1997;Cooper and Jan, 2003). Modulation of the M-current has profound effects on brain excitability because this noninactivating K ϩ channel exhibits significant conductance in the voltage range of action potential initiation. The low-threshold gating and the slow activation and deactivation of the M-current act as a brake for repetitive firing and neuronal excitability (

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Section: Discussionmentioning

confidence: 82%

Meclofenamic Acid and Diclofenac, Novel Templates of KCNQ2/Q3 Potassium Channel Openers, Depress Cortical Neuron Activity and Exhibit Anticonvulsant Properties

Peretz

Degani²,

Nachman³

et al. 2004

Mol Pharmacol

190

175

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“…In addition, isoflurane may suppress CSD by augmenting glutamate uptake in astrocytes (Miyazaki, et al, 1997), or reducing glutamate release (el-Beheiry and Puil, 1989, Kullmann, et al, 1989, Wu, et al, 2004. Another potential mechanism for CSD inhibition is membrane hyperpolarization via opening of K + channels (Wu, et al, 2003). Isoflurane, chloral hydrate, and N 2 O have been shown to activate TREK channels (Franks and Honore, 2004), which are background K + channels that clamp the membrane potential at resting levels thus resisting depolarization.…”

Section: Discussionmentioning

confidence: 99%

“…Various experimental models have been employed to assess CSD susceptibility, such as recording the frequency of CSDs evoked during continuous topical KCl application (Ayata, et al, 2006, Kitahara, et al, 2001, Read, et al, 1997, Richter, et al, 2002, Wu, et al, 2003. This model showed good clinical correlation.…”

Section: Introductionmentioning

confidence: 99%

The impact of anesthetics and hyperoxia on cortical spreading depression

Kudo

Nozari

Moskowitz

et al. 2008

Experimental Neurology

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Cortical spreading depression (CSD), a transient neuronal and glial depolarization that propagates slowly across the cerebral cortex, is the putative electrophysiological event underlying migraine aura. It negatively impacts tissue injury during stroke, cerebral contusion and intracranial hemorrhage. Susceptibility to CSD has been assessed in several experimental animal models in vivo, such as after topical KCl application or cathodal stimulation. Various combinations of anesthetics and ambient conditions have been used by different laboratories making comparisons problematic and differences in data difficult to reconcile. We systematically studied CSD susceptibility comparing commonly used experimental anesthetics (isoflurane, α-chloralose, urethane) with or without N 2 O or normobaric hyperoxia (100% O 2 inhalation). The frequency of evoked CSDs, and their propagation speed, duration, and amplitude were recorded during 2 hour topical KCl (1M) application. We found that N 2 O reduced CSD frequency when combined with isoflurane or urethane, but not α-chloralose; N 2 O also decreased CSD propagation speed and duration. Urethane anesthesia was associated with the highest CSD frequency that was comparable to pentobarbital. Inhalation of 100% O 2 did not alter CSD frequency, propagation speed or duration in combination with any of the anesthetics tested. Our data show anesthetic modulation of CSD susceptibility in an experimental model of human disease, underscoring the importance of proper study design for hypothesis testing as well as for comparing results between studies.

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“…Most of the compounds characterized so far augment currents mainly by shifting their voltage dependence of activation to less depolarized potentials (Rundfeldt and Netzer, 2000;Wickenden et al, 2000;Schroder et al, 2001;Wu et al, 2003), although a few augment currents in a voltage-independent manner (Dupuis et al, 2002). It is thought that by augmenting KCNQ channel activity, these drugs may be antiepileptic agents, or could otherwise strongly modify nervous function.…”

Section: Kcnq Kmentioning

confidence: 99%

Single-Channel Analysis of KCNQ K⁺Channels Reveals the Mechanism of Augmentation by a Cysteine-Modifying Reagent

Li¹,

Gamper²,

Shapiro³

2004

J. Neurosci.

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The cysteine-modifying reagent N-ethylmaleimide (NEM) is known to augment currents from native M-channels in sympathetic neurons and cloned KCNQ2 channels. As a probe for channel function, we investigated the mechanism of NEM action and subunit specificity of cloned KCNQ2-5 channels expressed in Chinese hamster ovary cells at the whole-cell and single-channel levels. Biotinylation assays and total internal reflection fluorescence microscopy indicated that NEM action is not caused by increased trafficking of channels to the membrane. At saturating voltages, whole-cell currents of KCNQ2, KCNQ4, and KCNQ5 but not KCNQ3 were augmented threefold to fourfold by 50 M NEM, and their voltage dependencies were negatively shifted by 10 -20 mV. Unitary conductances of KCNQ2 and KCNQ3 (6.2 and 8.5 pS, respectively) were much higher that those of KCNQ4 and KCNQ5 (2.1 and 2.2 pS, respectively). Surprisingly, the maximal open probability (P o ) of KCNQ3 was near unity, much higher than that of KCNQ2, KCNQ4, and KCNQ5. NEM increased the P o of KCNQ2, KCNQ4, and KCNQ5 by threefold to fourfold but had no effect on their unitary conductances, suggesting that the increase in macroscopic currents can be accounted for by increases in P o . Analysis of KCNQ3/4 chimeras determined the C terminus to be responsible for the differential maximal P o , channel expression, and NEM action between the two channels. To further localize the site of NEM action, we mutated three cysteine residues in the C terminus of KCNQ4. The C519A mutation alone ablated most of the augmentation by NEM, suggesting that NEM acts via alkylation of this residue.

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(S)-N-[1-(3-Morpholin-4-ylphenyl)ethyl]- 3-phenylacrylamide: An Orally Bioavailable KCNQ2 Opener with Significant Activity in a Cortical Spreading Depression Model of Migraine

Cited by 58 publications

References 19 publications

Meclofenamic Acid and Diclofenac, Novel Templates of KCNQ2/Q3 Potassium Channel Openers, Depress Cortical Neuron Activity and Exhibit Anticonvulsant Properties

Meclofenamic Acid and Diclofenac, Novel Templates of KCNQ2/Q3 Potassium Channel Openers, Depress Cortical Neuron Activity and Exhibit Anticonvulsant Properties

The impact of anesthetics and hyperoxia on cortical spreading depression

Single-Channel Analysis of KCNQ K⁺Channels Reveals the Mechanism of Augmentation by a Cysteine-Modifying Reagent

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(S)-N-[1-(3-Morpholin-4-ylphenyl)ethyl]- 3-phenylacrylamide: An Orally Bioavailable KCNQ2 Opener with Significant Activity in a Cortical Spreading Depression Model of Migraine

Cited by 58 publications

References 19 publications

Meclofenamic Acid and Diclofenac, Novel Templates of KCNQ2/Q3 Potassium Channel Openers, Depress Cortical Neuron Activity and Exhibit Anticonvulsant Properties

Meclofenamic Acid and Diclofenac, Novel Templates of KCNQ2/Q3 Potassium Channel Openers, Depress Cortical Neuron Activity and Exhibit Anticonvulsant Properties

The impact of anesthetics and hyperoxia on cortical spreading depression

Single-Channel Analysis of KCNQ K+Channels Reveals the Mechanism of Augmentation by a Cysteine-Modifying Reagent

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Single-Channel Analysis of KCNQ K⁺Channels Reveals the Mechanism of Augmentation by a Cysteine-Modifying Reagent