(S)-N-[1-(4-Cyclopropylmethyl-3,4-dihydro-2H-benzooxazin-6-yl)-ethyl]-3-(2-fluoro-phenyl)-acrylamide is a potent and efficacious KCNQ2 opener which inhibits induced hyperexcitability of rat hippocampal neurons

Wu, Yong‐Jin; Boissard, Christopher G.; Chen, Jie; Fitzpatrick, William; Gao, Qi; Gribkoff, Valentin K.; Harden, David G.; He, Huan; Knox, Ronald J.; Natale, Joanne; Pieschl, Rick L.; Starrett, John E.; Sun, Li‐Qiang; Thompson, M. D.; Weaver, David T.; Wu, Dedong; Dworetzky, Steven I.

doi:10.1016/j.bmcl.2004.01.069

Cited by 27 publications

(14 citation statements)

References 9 publications

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“…Because neuronal KCNQ activation may dampen membrane excitability and suppress action potential firing, the potentiation of these channels by chemical ligands is believed to be an important strategy for treating epilepsy (Surti and Jan 2005;Lawson and McKay 2006). Currently, more than 20 KCNQ activators have been reported (Schroder et al, 2001;Wu et al, 2003Wu et al, , 2004aPeretz et al, 2005;Xiong et al, 2008;Mruk and Kobertz 2009;Padilla et al, 2009;Gao et al, 2010). The subtype selectivity of these activators is varied.…”

Section: Introductionmentioning

confidence: 99%

P-Retigabine: An N-Propargyled Retigabine with Improved Brain Distribution and Enhanced Antiepileptic Activity

Zhou

Zhang

et al. 2014

Mol Pharmacol

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Retigabine (RTG,methyl] amino] phenyl] carbamate]) is a first-in-class antiepileptic drug that acts by potentiating neuronal KCNQ potassium channels; however, it has less than optimal brain distribution. In this study, we report that P-RTG (ethyl N-[2-amino-4-((4-fluorobenzyl) (prop-2-ynyl)amino)phenyl]carbamate), an RTG derivative that incorporates a propargyl group at the N position of the RTG linker, exhibits an inverted brain distribution compared with RTG. The brain-to-plasma concentration ratio of P-RTG increased to 2.30 compared with 0.16 for RTG. However, the structural modification did not change the drug's potentiation potency, subtype selectivity, or RTG molecular determinants on KCNQ channels. In addition, in cultured hippocampal neurons, P-RTG exhibited a similar capability as RTG for suppressing both induced and spontaneous action potential firing. Notably, P-RTG antiepileptic activity in the maximal electroshock (MES)-induced mouse seizure model was significantly enhanced to a value 2.5 times greater than that of RTG. Additionally, the neurotoxicity of P-RTG in the rotarod test was comparable with that of RTG. Collectively, our results indicate that the incorporation of a propargyl group significantly improves the RTG brain distribution, supporting P-RTG as a promising antiepileptic drug candidate. The strategy for improving brain-to-plasma distribution of RTG might be applicable for the drug development of other central nervous system diseases.

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Section: Introductionmentioning

confidence: 99%

P-Retigabine: An N-Propargyled Retigabine with Improved Brain Distribution and Enhanced Antiepileptic Activity

Zhou

Zhang

et al. 2014

Mol Pharmacol

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“…(S)-2 was prepared according to a literature procedure [23]. Synthesis of SMB-1 ((E)-N-[(S)-1-(4-Cyclopropylmethyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-ethyl]-3-(2-fluoro-phenyl)-N-methyl-acrylamide): To a solution of (S)-2 (100 mg, 262.8 µmol) in a mixture of anhydrous tetrahydrofuran (THF, 1.5 mL) and dimethylformamide (DMF, 0.3 mL) at 0°C was added NaH (16 mg, 394 µmol, 60% dispersion in mineral oil) and MeI (17.8 µL, 289 µmol).…”

Section: Methodsmentioning

confidence: 99%

From Pan-Reactive KV7 Channel Opener to Subtype Selective Opener/Inhibitor by Addition of a Methyl Group

Blom

Rottländer²,

Kehler³

et al. 2014

PLoS ONE

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The voltage-gated potassium channels of the KV7 family (KV7.1–5) play important roles in controlling neuronal excitability and are therefore attractive targets for treatment of CNS disorders linked to hyperexcitability. One of the main challenges in developing KV7 channel active drugs has been to identify compounds capable of discriminating between the neuronally expressed subtypes (KV7.2–5), aiding the identification of the subunit composition of KV7 currents in various tissues, and possessing better therapeutic potential for particular indications. By taking advantage of the structure-activity relationship of acrylamide KV7 channel openers and the effects of these compounds on mutant KV7 channels, we have designed and synthesized a novel KV7 channel modulator with a unique profile. The compound, named SMB-1, is an inhibitor of KV7.2 and an activator of KV7.4. SMB-1 inhibits KV7.2 by reducing the current amplitude and increasing the time constant for the slow component of the activation kinetics. The activation of KV7.4 is seen as an increase in the current amplitude and a slowing of the deactivation kinetics. Experiments studying mutant channels with a compromised binding site for the KV7.2–5 opener retigabine indicate that SMB-1 binds within the same pocket as retigabine for both inhibition of KV7.2 and activation of KV7.4. SMB-1 may serve as a valuable tool for KV7 channel research and may be used as a template for further design of better subtype selective KV7 channel modulators. A compound with this profile could hold novel therapeutic potential such as the treatment of both positive and cognitive symptoms in schizophrenia.

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“…These two compounds are effective antiepileptic agents in vivo (Peretz et al 2005). Acrylamide (S)-1 potently activates Kv7.2 and also dampens hyperexcitation in rat hippocampus neurons (Wu et al 2004). The above-mentioned compounds share the common features of modifying Kv7 channel gating by causing a hyperpolarizing shift in activation V 1/2 and/or slowing the deactivation rate (Xiong et al 2008).…”

Section: Kv7 Channel Activators and Modulation Of Hyperexcitabilitymentioning

confidence: 98%

Voltage-gated K+ channel modulators as neuroprotective agents

Leung

2010

Life Sciences

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(S)-N-[1-(4-Cyclopropylmethyl-3,4-dihydro-2H-benzooxazin-6-yl)-ethyl]-3-(2-fluoro-phenyl)-acrylamide is a potent and efficacious KCNQ2 opener which inhibits induced hyperexcitability of rat hippocampal neurons

Cited by 27 publications

References 9 publications

P-Retigabine: An N-Propargyled Retigabine with Improved Brain Distribution and Enhanced Antiepileptic Activity

P-Retigabine: An N-Propargyled Retigabine with Improved Brain Distribution and Enhanced Antiepileptic Activity

From Pan-Reactive KV7 Channel Opener to Subtype Selective Opener/Inhibitor by Addition of a Methyl Group

Voltage-gated K+ channel modulators as neuroprotective agents

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