A Selective Na<sub>v</sub>1.8 Sodium Channel Blocker, A-803467 [5-(4-Chlorophenyl-<i>N</i>-(3,5-dimethoxyphenyl)furan-2-carboxamide], Attenuates Spinal Neuronal Activity in Neuropathic Rats

McGaraughty, Steve; Chu, Katharine L.; Scanio, Marc J. C.; Kort, Michael E.; Faltynek, Connie R.; Jarvis, Michael F.

doi:10.1124/jpet.107.134148

Cited by 75 publications

(59 citation statements)

References 40 publications

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“…Furthermore, this compound was shown to reduce neuropathic and inflammatory pain in animal models (McGaraughty et al, 2008). Here, we demonstrate that A803467 also blocks T-type channels with high affinity, with IC50 values that fall into the range of therapeutic concentrations and that block of the Ca v 3.2 channel subtype seems to stabilize slow inactivation.…”

Section: Discussionmentioning

confidence: 78%

“…Indeed, knock-out of Na v 1.8 and Ca v 3.2 results in hyposensitivity to pain (for reviews, see Wang et al, 2011;Cregg et al, 2010), suggesting the possibility that mixed Na v /T-type channel blockers may be a possible strategy for the development of new analgesics (Hildebrand et al, 2010). 5-(4-Chlorophenyl-N-(3,5-dimethoxyphenyl)furan-2-carboxamide (A803467), a new inhibitor of Na v 1.8 channels, has been shown to be efficacious in animal pain models (McGaraughty et al, 2008). The interaction site of A803467 on the Na v channel complex is unknown, but its mode of action seems to be preferential binding to the slow inactivated state of this channel (Jarvis et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Common Mechanisms of Drug Interactions with Sodium and T-Type Calcium Channels

Bladen¹,

Zamponi²

2012

Mol Pharmacol

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Voltage-gated sodium (Na v ) and calcium (Ca v ) channels play important roles in physiological processes, including neuronal and cardiac pacemaker activity, vascular smooth muscle contraction, and nociception. They are thought to share a common ancestry, and, in particular, T-type calcium (T-type) channels share structural similarities with Na v channels, both with regard to membrane topology and with regard to gating kinetics, including rapid inactivation. We thus reasoned that certain drugs acting on Na v channels may also modulate the activities of T-type channels. Here we show that the specific Na v 1.8 blocker 5-(4-chlorophenyl-N-(3,5-dimethoxyphenyl)furan-2-carboxamide (A803467) tonically blocks T-type channels in the low micromolar range. Similarly to Na v 1.8, this compound causes a significant hyperpolarizing shift in the voltage dependence of inactivation and seems to promote a slow inactivation-like phenotype. We further hypothesized that the structural similarity between T-type and Na v channels may extend to structurally similar drug-binding sites. Sequence alignment revealed several highly conserved regions between T-type and Na v channels that corresponded to drug-binding sites known to alter voltage-dependent gating kinetics. Mutation of amino acid residues in this regions within human Ca v 3.2 T-type channels altered A803467 blocking affinity severalfold, suggesting that these sites may be exploited for the design of mixed T-type and Na v channel blockers that could potentially act synergistically to normalize aberrant neuronal activity.

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Section: Discussionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Common Mechanisms of Drug Interactions with Sodium and T-Type Calcium Channels

Bladen¹,

Zamponi²

2012

Mol Pharmacol

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“…Additionally, multiple inflammatory mediators have been described as potential modulators of the expression and activity of some Na v isoforms, especially Na v 1.8 18 . markedly, a selective Na v 1.8 blocker (A-803467) was antinociceptive in animal models with inflammatory pain 19 and NP 20 . Animal studies have shown that neuromas formed after nervous injury may induce ectopic generation of spontaneous potential impulses and firings 9 , closely related to increased Na v 1.3 expression 21 .…”

Section: Electric Potential Difference-gated Sodium Chan-nels (Na V )mentioning

confidence: 99%

Behavior of ion channels controlled by electric potential difference and of Toll-type receptors in neuropathic pain pathophysiology

Schmidt¹,

Schmidt²

2016

Revista Dor

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BACKGROUND AND OBJECTIVES:Neuropathic pain is a severe and refractory medical condition, for which only partially effective treatments are currently available. Recent experimental data on the role of voltage-gated ion channels, particularly sodium and potassium channels, have been described. In this brief review, we aimed at addressing the role of sodium and potassium channels in the pathophysiology of neuropathic pain and recent evidences about their role as a new therapeutic target in painful conditions. CONTENTS: Pharmacological and biophysical studies have shown that voltagegated sodium channels, particularly Na v 1.3, Na v 1.7, Na v 1.8, and Na v 1.9 isoforms are important in the pathophysiology of neuropathic pain. Similarly, the involvement of voltage-gated potassium channels, especially K V 1 and K V 7 isoforms, has been clearly shown in the establishment of chronic painful conditions. Recent evidences that ion sodium and potassium channels dysfunction is involved in the development of chronic painful conditions corroborate the possibility of pharmacologically modulate them as new therapeutic strategies. CONCLUSION: Recent evidences suggest that selective sodium channel blockers and potassium channels activating of modulating drugs are important and promising targets in the search for new options to treat neuropathic pain. Keywords: Chronic pain, Ion channels, Neuropathic pain, Potassium channels, Sodium channels. RESUMO JUSTIFICATIVA E OBJETIVOS:A dor neuropática constitui-se em uma condição clínica grave e refratária, para a qual apenas tratamentos com eficácia parcial estão disponíveis. Estudos experimentais recentes sobre o papel relevante de canais iônicos controlados por diferença de potencial elétrico ou voltagem, especialmente canais de sódio e potássio, tem sido descritos. Nesta breve revisão, objetivou-se abordar o papel dos canais de sódio e potássio na fisiopatologia da dor neuropática e as recentes evidências a respeito do seu papel como novo alvo terapêutico em quadros dolorosos. CONTEÚDO: Estudos farmacológicos e biofísicos tem demonstrado que os canais de sódio dependentes de voltagem, particularmente as isoformas Na v 1.3, Na v 1.7, Na v 1.8 e Na v 1.9 são relevantes na fisiopatologia da dor neuropática. De forma similar, o envolvimento dos canais de potássio dependentes de voltagem, especialmente as isoformas K v 1 e K v 7, tem sido claramente demonstrado no estabelecimento de quadros dolorosos crônicos. As evidências recentes de que a disfunção de canais iônicos de sódio e potássio está envolvida no desenvolvi- Behavior of ion channels controlled by electric potential difference and of Toll-type receptors in neuropathic pain pathophysiology O comportamento dos canais iônicos controlados por diferença de potencial elétrico e dos receptores do tipo Toll na fisiopatologia da dor neuropática

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“…In mice, knocking down the Na(v)1.8 gene by antisense oligonucleotides attenuated the development of inflammatory hyperalgesia [52,53]. Currently A-803467, a Na(v)1.8-selective blocker, has been shown to attenuate mechanical allodynia in a dosedependent fashion in animal pain models including sciatic nerve injury, spinal nerve ligation, and chemically induced thermal allodynia and secondary allodynia [51,54]. Ambroxol, a relatively selective blocker of Na(v)1.8. has also been shown to produce effective analgesia in inflammatory and neuropathic pain models in animals [55].…”

Section: Intracellular Space Extracellular Spacementioning

confidence: 99%

C-fiber-Selective Peripheral Nerve Blockade

Suzuki¹,

Gerner²,

Colvin³

et al. 2009

TOPAINJ

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Despite the clinical demand, current uses of local anesthetics do not allow selective blockade of nociceptive fibers. Regional anesthesia produces an analgesic effect accompanied with undesired side effects due to block of motor, non-nociceptive sensory and autonomic fibers. These side effects limit the clinical use of local anesthetics and affect the recovery and rehabilitation period after surgical procedures. Therefore one main goal of research in the field of regional anesthesia is selectively targeting nociceptive fibers. Recent studies describing the role of nociceptive specific sodium channels in generation and propagation of nociceptive signals make these channels ideal targets for pain selective blockade. In addition, novel methods of targeted delivery of charged local anesthetics selectively into nociceptors provide another potentially successful approach for c-fiber specific nerve block. This review summarizes currently on-going studies on several promising targets and methods to achieve pain selective anesthesia.

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A Selective Na_v1.8 Sodium Channel Blocker, A-803467 [5-(4-Chlorophenyl-N-(3,5-dimethoxyphenyl)furan-2-carboxamide], Attenuates Spinal Neuronal Activity in Neuropathic Rats

Cited by 75 publications

References 40 publications

Common Mechanisms of Drug Interactions with Sodium and T-Type Calcium Channels

Common Mechanisms of Drug Interactions with Sodium and T-Type Calcium Channels

Behavior of ion channels controlled by electric potential difference and of Toll-type receptors in neuropathic pain pathophysiology

C-fiber-Selective Peripheral Nerve Blockade

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A Selective Nav1.8 Sodium Channel Blocker, A-803467 [5-(4-Chlorophenyl-N-(3,5-dimethoxyphenyl)furan-2-carboxamide], Attenuates Spinal Neuronal Activity in Neuropathic Rats

Cited by 75 publications

References 40 publications

Common Mechanisms of Drug Interactions with Sodium and T-Type Calcium Channels

Common Mechanisms of Drug Interactions with Sodium and T-Type Calcium Channels

Behavior of ion channels controlled by electric potential difference and of Toll-type receptors in neuropathic pain pathophysiology

C-fiber-Selective Peripheral Nerve Blockade

Contact Info

Product

Resources

About

A Selective Na_v1.8 Sodium Channel Blocker, A-803467 [5-(4-Chlorophenyl-N-(3,5-dimethoxyphenyl)furan-2-carboxamide], Attenuates Spinal Neuronal Activity in Neuropathic Rats