Discovery of a novel Kv7 channel opener as a treatment for epilepsy

Davoren, Jennifer E.; Claffey, Michelle M.; Snow, Sheri L.; Reese, Matthew R.; Arora, Gaurav; Butler, Christopher R.; Boscoe, Brian P.; Chenard, Lois K.; DeNinno, Shari L.; Drozda, Susan E.; Duplantier, Allen J.; Moine, Ludivine; Rogers, Bruce N.; Rong, Suo-Bao; Schuyten, Katherine; Wright, Ann S.; Zhang, Lei; Serpa, Kevin A.; Weber, Mark L.; Stolyar, Polina; Whisman, Tammy; Baker, Karen; Tse, Karen; Clark, Alan; Rong, Haojing; Mather, Robert J.; Lowe, John

doi:10.1016/j.bmcl.2015.04.074

Cited by 18 publications

(10 citation statements)

References 19 publications

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“…Several groups have performed structure–activity relationship (SAR) analyses of retigabine to produce more potent and selective derivatives. Thus, compounds PF‐05020182 (Figure C) (Davoren et al, ) and NS15370 (Figure D) (Dalby‐Brown et al, ), which are ~10 and ~30 fold more potent than retigabine, were synthesized; these are ineffective against K v 7.1 but do activate K v 7.4 and K v 7.5 channels with comparable potency to that of K v 7.2/K v 7.3. Thanos Tzounopoulos' group used the SAR approach to generate several improved retigabine derivatives.…”

Section: Channel Openersmentioning

confidence: 99%

M‐type K⁺ channels in peripheral nociceptive pathways

Gao

Jaffe

et al. 2017

British J Pharmacology

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Pathological pain is a hyperexcitability disorder. Since the excitability of a neuron is set and controlled by a complement of ion channels it expresses, in order to understand and treat pain, we need to develop a mechanistic insight into the key ion channels controlling excitability within the mammalian pain pathways and how these ion channels are regulated and modulated in various physiological and pathophysiological settings. In this review, we will discuss the emerging data on the expression in pain pathways, functional role and modulation of a family of voltage‐gated K+ channels called ‘M channels’ (KCNQ, Kv7). M channels are increasingly recognized as important players in controlling pain signalling, especially within the peripheral somatosensory system. We will also discuss the therapeutic potential of M channels as analgesic drug targets.Linked ArticlesThis article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc/

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Section: Channel Openersmentioning

confidence: 99%

M‐type K⁺ channels in peripheral nociceptive pathways

Gao

Jaffe

et al. 2017

British J Pharmacology

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“…Several KCNQ channel openers are under active development for the management of hyperexcitability disorders (Dalby-Brown et al, 2013;Grunnet et al, 2014;Stott et al, 2014;Davoren et al, 2015). Retigabine, which activates all KCNQ2-5 channels, is the only anticonvulsant KCNQ activator that has been approved by the U.S. Food and Drug Administration (FDA) (Tatulian et al, 2001;Gunthorpe et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of Potent KCNQ2/3-Specific Channel Activators

et al. 2016

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KQT-like subfamily (KCNQ) channels are voltage-gated, noninactivating potassium ion channels, and their down-regulation has been implicated in several hyperexcitability-related disorders, including epilepsy, neuropathic pain, and tinnitus. Activators of these channels reduce the excitability of central and peripheral neurons, and, as such, have therapeutic utility. Here, we synthetically modified several moieties of the KCNQ2-5 channel activator retigabine, an anticonvulsant approved by the U.S. Food and Drug Administration. By introducing a CF 3 -group at the 4-position of the benzylamine moiety, combined with a fluorine atom at the 3-position of the aniline ring, we generated Ethyl (2-amino-3-fluoro-4-((4-(trifluoromethyl)benzyl)amino)phenyl)carbamate (RL648_81), a new KCNQ2/3-specific activator that is .15 times more potent and also more selective than retigabine. We suggest that RL648_81 is a promising clinical candidate for treating or preventing neurologic disorders associated with neuronal hyperexcitability.

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“…Activation of neuronal Kv7/KCNQ/M-channels by the opener QO58-lysine and its anti-nociceptive effects on inflammatory pain in rodents 1055 www.chinaphar.com Teng BC et al Acta Pharmacologica Sinica channel openers, such as zinc pyrithione, which can rescue the channel mutants [18] , and PF-05020182, which suppresses convulsions in animals [19] . We recently designed and synthesized a novel series of pyrazolo [1, 5-a]pyrimidin-7(4H)-ones (PPOs) that can selectively activate KCNQ/M-channels [20] .…”

Section: Original Articlementioning

confidence: 99%

“…Rodent models of pain Adult male SD rats (200-220 g) and the ICR mice (18)(19)(20)(21)(22) Formalin-induced pain in mice Formalin (5% methanol solution, 10 μL) was carefully injected into the plantar surface of the hindpaw using a microsyringe. After injection, licking and biting behaviors were measured.…”

Section: Pharmacokinetic Analysismentioning

confidence: 99%

Activation of neuronal Kv7/KCNQ/M-channels by the opener QO58-lysine and its anti-nociceptive effects on inflammatory pain in rodents

et al. 2016

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Aim: The aim of this study was to examine the activation of neuronal Kv7/KCNQ channels by a novel modified Kv7 opener QO58-lysine and to test the anti-nociceptive effects of QO58-lysine on inflammatory pain in rodent models. Methods: Assays including whole-cell patch clamp recordings, HPLC, and in vivo pain behavioral evaluations were employed. Results: QO58-lysine caused instant activation of Kv7.2/7.3 currents, and increasing the dose of QO58-lysine resulted in a dosedependent activation of Kv7.2/Kv7.3 currents with an EC 50 of 1.2±0.2 μmol/L. QO58-lysine caused a leftward shift of the voltagedependent activation of Kv7.2/Kv7.3 to a hyperpolarized potential at V 1/2 =-54.4±2.5 mV from V 1/2 =-26.0±0.6 mV. The half-life in plasma (t 1/2 ) was derived as 2.9, 2.7, and 3.0 h for doses of 12.5, 25, and 50 mg/kg, respectively. The absolute bioavailabilities for the three doses (12.5, 25, and 50 mg/kg) of QO58-lysine (po) were determined as 13.7%, 24.3%, and 39.3%, respectively. QO58-lysine caused a concentration-dependent reduction in the licking times during phase II pain induced by the injection of formalin into the mouse hindpaw. In the Complete Freund's adjuvant (CFA)-induced inflammatory pain model in rats, oral or intraperitoneal administration of QO58-lysine resulted in a dose-dependent increase in the paw withdrawal threshold, and the anti-nociceptive effect on mechanical allodynia could be reversed by the channel-specific blocker XE991 (3 mg/kg). Conclusion: Taken together, our findings show that a modified QO58 compound (QO58-lysine) can specifically activate Kv7.2/7.3/ M-channels. Oral or intraperitoneal administration of QO58-lysine, which has improved bioavailability and a half-life of approximately 3 h in plasma, can reverse inflammatory pain in rodent animal models.

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Discovery of a novel Kv7 channel opener as a treatment for epilepsy

Cited by 18 publications

References 19 publications

M‐type K⁺ channels in peripheral nociceptive pathways

M‐type K⁺ channels in peripheral nociceptive pathways

Synthesis and Evaluation of Potent KCNQ2/3-Specific Channel Activators

Activation of neuronal Kv7/KCNQ/M-channels by the opener QO58-lysine and its anti-nociceptive effects on inflammatory pain in rodents

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Discovery of a novel Kv7 channel opener as a treatment for epilepsy

Cited by 18 publications

References 19 publications

M‐type K+ channels in peripheral nociceptive pathways

M‐type K+ channels in peripheral nociceptive pathways

Synthesis and Evaluation of Potent KCNQ2/3-Specific Channel Activators

Activation of neuronal Kv7/KCNQ/M-channels by the opener QO58-lysine and its anti-nociceptive effects on inflammatory pain in rodents

Contact Info

Product

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M‐type K⁺ channels in peripheral nociceptive pathways

M‐type K⁺ channels in peripheral nociceptive pathways