Characterization of Vixotrigine, a Broad-Spectrum Voltage-Gated Sodium Channel Blocker

Hinckley, Christopher A.; Kuryshev, Yuri A.; Sers, Alissende; Barre, Annick; Naik, Himanshu; Hajós, Mihály

doi:10.1124/molpharm.120.000079

Cited by 19 publications

(25 citation statements)

References 32 publications

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“…At a pulse frequency of 40 Hz, sTsp1a superficially appears to be a more potent inhibitor of hNa V 1.7 (Figure E), but the level of current inhibition, relative to the control, was not enhanced compared to that of 0.1 Hz stimulation (Figure E). High-frequency pulsing did not lead to a cumulative increase in channel inhibition relative to the control, a feature that is characteristic of use-dependent small-molecule Na V channel inhibitors such as lidocaine, chlorpromazine, and vixotrigine . When applied to partially inactivated channels, sTsp1a was in fact a less potent inhibitor (IC 50 = 64.0 ± 3.6 nM; n = 3; Figure F) than when applied to closed/resting state channels (IC 50 = 10.3 nM; Figure ).…”

Section: Resultsmentioning

confidence: 91%

“…High-frequency pulsing did not lead to a cumulative increase in channel inhibition relative to the control, a feature that is characteristic of use-dependent small-molecule Na V channel inhibitors such as lidocaine, 29 chlorpromazine, 30 and vixotrigine. 31 When applied to partially inactivated channels, sTsp1a was in fact a less potent inhibitor (IC 50 = 64.0 ± 3.6 nM; n = 3; Figure 4F) than when applied to closed/resting state channels (IC 50 = 10.3 nM; Figure 3). Thus, sTsp1a potency is not enhanced in a use-dependent manner.…”

Section: ■ Resultsmentioning

confidence: 94%

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Pharmacological Inhibition of the Voltage-Gated Sodium Channel Na_V1.7 Alleviates Chronic Visceral Pain in a Rodent Model of Irritable Bowel Syndrome

Jiang

Castro

Blomster

et al. 2021

ACS Pharmacol. Transl. Sci.

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The human nociceptor-specific voltage-gated sodium channel 1.7 (hNaV1.7) is critical for sensing various types of somatic pain, but it appears not to play a primary role in acute visceral pain. However, its role in chronic visceral pain remains to be determined. We used assay-guided fractionation to isolate a novel hNaV1.7 inhibitor, Tsp1a, from tarantula venom. Tsp1a is 28-residue peptide that potently inhibits hNaV1.7 (IC50 = 10 nM), with greater than 100-fold selectivity over hNaV1.3–hNaV1.6, 45-fold selectivity over hNaV1.1, and 24-fold selectivity over hNaV1.2. Tsp1a is a gating modifier that inhibits NaV1.7 by inducing a hyperpolarizing shift in the voltage-dependence of channel inactivation and slowing recovery from fast inactivation. NMR studies revealed that Tsp1a adopts a classical knottin fold, and like many knottin peptides, it is exceptionally stable in human serum. Remarkably, intracolonic administration of Tsp1a completely reversed chronic visceral hypersensitivity in a mouse model of irritable bowel syndrome. The ability of Tsp1a to reduce visceral hypersensitivity in a model of irritable bowel syndrome suggests that pharmacological inhibition of hNaV1.7 at peripheral sensory nerve endings might be a viable approach for eliciting analgesia in patients suffering from chronic visceral pain.

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Section: Resultsmentioning

confidence: 91%

Section: ■ Resultsmentioning

confidence: 94%

Pharmacological Inhibition of the Voltage-Gated Sodium Channel Na_V1.7 Alleviates Chronic Visceral Pain in a Rodent Model of Irritable Bowel Syndrome

Jiang

Castro

Blomster

et al. 2021

ACS Pharmacol. Transl. Sci.

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“…The first is the Na v 1.7 blocker, vixotrigine (CNV1014802, BIIB074, or GSK-1014802) ( 184 , 185 ). The outcomes of a phase III clinical trial for effectiveness in trigeminal neuralgia (NCT03637387) and phase II trial for small fiber neuropathy are eagerly awaited ( 47 ).…”

Section: Discussionmentioning

confidence: 99%

“…Another broad spectrum non-sulfonamide Na v blocker, vixotrigine, which was previously known as raxatrigine, or CNV1014802, BIIB074, or GSK-1014802 ( 184 ), has shown effectiveness in animal models of Na v 1.7-dependent pain. Its safety in human patients has been established ( 185 ).…”

Section: Voltage-gated Na + Channelsmentioning

confidence: 99%

Peripheral Voltage-Gated Cation Channels in Neuropathic Pain and Their Potential as Therapeutic Targets

Alles

Smith

2021

Front. Pain Res.

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The persistence of increased excitability and spontaneous activity in injured peripheral neurons is imperative for the development and persistence of many forms of neuropathic pain. This aberrant activity involves increased activity and/or expression of voltage-gated Na+ and Ca2+ channels and hyperpolarization activated cyclic nucleotide gated (HCN) channels as well as decreased function of K+ channels. Because they display limited central side effects, peripherally restricted Na+ and Ca2+ channel blockers and K+ channel activators offer potential therapeutic approaches to pain management. This review outlines the current status and future therapeutic promise of peripherally acting channel modulators. Selective blockers of Nav1.3, Nav1.7, Nav1.8, Cav3.2, and HCN2 and activators of Kv7.2 abrogate signs of neuropathic pain in animal models. Unfortunately, their performance in the clinic has been disappointing; some substances fail to meet therapeutic end points whereas others produce dose-limiting side effects. Despite this, peripheral voltage-gated cation channels retain their promise as therapeutic targets. The way forward may include (i) further structural refinement of K+ channel activators such as retigabine and ASP0819 to improve selectivity and limit toxicity; use or modification of Na+ channel blockers such as vixotrigine, PF-05089771, A803467, PF-01247324, VX-150 or arachnid toxins such as Tap1a; the use of Ca2+ channel blockers such as TTA-P2, TTA-A2, Z 944, ACT709478, and CNCB-2; (ii) improving methods for assessing “pain” as opposed to nociception in rodent models; (iii) recognizing sex differences in pain etiology; (iv) tailoring of therapeutic approaches to meet the symptoms and etiology of pain in individual patients via quantitative sensory testing and other personalized medicine approaches; (v) targeting genetic and biochemical mechanisms controlling channel expression using anti-NGF antibodies such as tanezumab or re-purposed drugs such as vorinostat, a histone methyltransferase inhibitor used in the management of T-cell lymphoma, or cercosporamide a MNK 1/2 inhibitor used in treatment of rheumatoid arthritis; (vi) combination therapy using drugs that are selective for different channel types or regulatory processes; (vii) directing preclinical validation work toward the use of human or human-derived tissue samples; and (viii) application of molecular biological approaches such as clustered regularly interspaced short palindromic repeats (CRISPR) technology.

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“…However, the high sequence homology among Na V isoforms in the central pore cavity has created challenges for developing selective compounds targeting this site. Investigational compounds such as Vixotrigine (Convergence/Biogen) targeting Na V 1.7 ( Hinckley et al, 2021 ), currently in phase II clinical trials for trigeminal neuralgia and small fiber neuropathy or PF-01247324 (Pfizer) ( Payne et al, 2015 ), PF-04531083 (Pfizer) ( Bagal et al, 2014 ) targeting Na V 1.8 are non-selective or have modest selectivity against the on-target channel. Another Na V 1.8 targeting compound, A-803467 (Abbott/Icagen) also binds to the T-type calcium channel in low micromolar affinity, within the range of therapeutic concentration ( Bladen and Zamponi, 2012 ).…”

Section: Current Efforts In the Development Of Pain Therapeutics Targ...mentioning

confidence: 99%

Towards Structure-Guided Development of Pain Therapeutics Targeting Voltage-Gated Sodium Channels

Nguyen

Yarov‐Yarovoy

2022

Front. Pharmacol.

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Voltage-gated sodium (NaV) channels are critical molecular determinants of action potential generation and propagation in excitable cells. Normal NaV channel function disruption can affect physiological neuronal signaling and lead to increased sensitivity to pain, congenital indifference to pain, uncoordinated movement, seizures, or paralysis. Human genetic studies have identified human NaV1.7 (hNaV1.7), hNaV1.8, and hNaV1.9 channel subtypes as crucial players in pain signaling. The premise that subtype selective NaV inhibitors can reduce pain has been reinforced through intensive target validation and therapeutic development efforts. However, an ideal therapeutic has yet to emerge. This review is focused on recent progress, current challenges, and future opportunities to develop NaV channel targeting small molecules and peptides as non-addictive therapeutics to treat pain.

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Characterization of Vixotrigine, a Broad-Spectrum Voltage-Gated Sodium Channel Blocker

Cited by 19 publications

References 32 publications

Pharmacological Inhibition of the Voltage-Gated Sodium Channel Na_V1.7 Alleviates Chronic Visceral Pain in a Rodent Model of Irritable Bowel Syndrome

Pharmacological Inhibition of the Voltage-Gated Sodium Channel Na_V1.7 Alleviates Chronic Visceral Pain in a Rodent Model of Irritable Bowel Syndrome

Peripheral Voltage-Gated Cation Channels in Neuropathic Pain and Their Potential as Therapeutic Targets

Towards Structure-Guided Development of Pain Therapeutics Targeting Voltage-Gated Sodium Channels

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Characterization of Vixotrigine, a Broad-Spectrum Voltage-Gated Sodium Channel Blocker

Cited by 19 publications

References 32 publications

Pharmacological Inhibition of the Voltage-Gated Sodium Channel NaV1.7 Alleviates Chronic Visceral Pain in a Rodent Model of Irritable Bowel Syndrome

Pharmacological Inhibition of the Voltage-Gated Sodium Channel NaV1.7 Alleviates Chronic Visceral Pain in a Rodent Model of Irritable Bowel Syndrome

Peripheral Voltage-Gated Cation Channels in Neuropathic Pain and Their Potential as Therapeutic Targets

Towards Structure-Guided Development of Pain Therapeutics Targeting Voltage-Gated Sodium Channels

Contact Info

Product

Resources

About

Pharmacological Inhibition of the Voltage-Gated Sodium Channel Na_V1.7 Alleviates Chronic Visceral Pain in a Rodent Model of Irritable Bowel Syndrome

Pharmacological Inhibition of the Voltage-Gated Sodium Channel Na_V1.7 Alleviates Chronic Visceral Pain in a Rodent Model of Irritable Bowel Syndrome