The discovery of benzoxazine sulfonamide inhibitors of Na V 1.7: Tools that bridge efficacy and target engagement

La, Daniel S.; Peterson, Emily A.; Bode, Christiane; Boezio, Alessandro A.; Bregman, Howard; Chu-Moyer, Margaret Y.; Coats, James; DiMauro, Erin F.; Dineen, Thomas A.; Du, Bingfan; Gao, Hua; Graceffa, Russell F.; Günaydın, Hakan; Guzmán-Pérez, Angel; Fremeau, Robert T.; Huang, Xin; Ilch, Christopher P; Kornecook, Thomas; Kreiman, Charles R.; Ligutti, Joseph; Lin, Min-Hwa Jasmine; McDermott, Jeff S.; Marx, Isaac E.; Matson, David J.; McDonough, Stefan I.; Moyer, Bryan D.; Nguyen, Hanh Nho; Taborn, Kristin; Yu, Violeta; Weiss, Matthew M.

doi:10.1016/j.bmcl.2017.05.070

Cited by 18 publications

(15 citation statements)

References 32 publications

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“…In agreement with previous studies, we show that a deletion or inhibition of one Na V channel is not sufficient to fully abolish scratching in mice 28,[30][31][32][33] . The contribution of several Na V channels to acute itch signalling of different stimuli, shown here, supports the suggestion that a simultaneous inhibition of different Na V channels is required to reach full abolishment.…”

Section: Discussionsupporting

confidence: 92%

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Complementary roles of murine NaV1.7, NaV1.8 and NaV1.9 in acute itch signalling

Kühn

Kappes

Wolf

et al. 2020

Sci Rep

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Acute pruritus occurs in various disorders. Despite severe repercussions on quality of life treatment options remain limited. Voltage-gated sodium channels (Na V ) are indispensable for transformation and propagation of sensory signals implicating them as drug targets. Here, Na V 1.7, 1.8 and 1.9 were compared for their contribution to itch by analysing Na V -specific knockout mice. Acute pruritus was induced by a comprehensive panel of pruritogens (C48/80, endothelin, 5-HT, chloroquine, histamine, lysophosphatidic acid, trypsin, SLIGRL, β-alanine, BAM8-22), and scratching was assessed using a magnet-based recording technology. We report an unexpected stimulus-dependent diversity in Na V channel-mediated itch signalling. Na V 1.7 −/− showed substantial scratch reduction mainly towards strong pruritogens. Na V 1.8 −/− impaired histamine and 5-HT-induced scratching while Na V 1.9 was involved in itch signalling towards 5-HT, C48/80 and SLIGRL. Furthermore, similar microfluorimetric calcium responses of sensory neurons and expression of itch-related TRP channels suggest no change in sensory transduction but in action potential transformation and conduction. The cumulative sum of scratching over all pruritogens confirmed a leading role of Na V 1.7 and indicated an overall contribution of na V 1.9. Beside the proposed general role of Na V 1.7 and 1.9 in itch signalling, scrutiny of time courses suggested Na V 1.8 to sustain prolonged itching. Therefore, Na V 1.7 and 1.9 may represent targets in pruritus therapy.Pruritus, commonly also referred to as itch, can appear as agonizing symptom of dermatological, systemic and psychogenic disorders 1 . Despite its high impact on the quality of life, treatment options remain limited. One obstacle in the development of new drugs arises from the diversity of signalling pathways triggering itch. Aside histamine, which was the first known pruritogen 2,3 , pruritus can be elicited by various histamine-independent pruritogens with diverse chemical structures acting on a wide range of receptors. A major role in histamine-independent itch signalling can be attributed to Mas-related G protein-coupled receptors (MRGPR). This family of G protein-coupled receptors (GPCRs) mediates acute scratch behaviour towards pruritogens such as bovine adrenal medulla 8-22 peptide (BAM8-22) 4 , chloroquine 5 , β-alanine 6 and the tethered PAR2 ligand SLIGRL 7 . Additionally, pruritogens like 5-hydroxytryptamine (5-HT) 8 , and lysophosphatidic acid (LPA) 9 signal via activation of their specific receptors.Pruritogens can activate GPCRs located on nerve endings of unmyelinated primary sensory neurons, resulting in a rise of cytosolic calcium levels both via the inositol phospholipid signalling pathway 10-13 and via transient receptor potential ion channels (TRP) 14 . Upon membrane depolarization, voltage-gated sodium channels (Na V ) are opened, triggering the initiation and propagation of action potentials. The function of Na V channels is determined by the pore-forming alpha-subunit of which nine subtyp...

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Section: Discussionsupporting

confidence: 92%

“…Corresponding inhibitory studies analysed the role of Na V subtypes in itch signalling. Inhibition of Na V 1.7 reduced acute scratch behaviour in mice upon histamine and selected non-histaminergic stimuli 19,[30][31][32][33] . Moreover, Na V 1.9 knockout mice showed reduced scratch behaviour upon treatment with histamine, chloroquine and BAM8-22 28 .…”

mentioning

confidence: 95%

Complementary roles of murine NaV1.7, NaV1.8 and NaV1.9 in acute itch signalling

Kühn

Kappes

Wolf

et al. 2020

Sci Rep

View full text Add to dashboard Cite

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“…This raises four possible explanations: first, that the drugs did not completely block Na V 1.7 channels; second, that blocking some 40% of itch C-fibers is sufficient to inhibit all evoked scratching in the mouse; third, that deleting Na V 1.7 led to the modulation of other relevant genes (e.g., see Minett et al, 2015); and fourth, that blocking Na V 1.7 in extracutaneous aspects of the nerve is more effective in inhibiting AP conduction in itch C-fibers than what is observed within the skin. Sulfonamide-based Na V 1.7 blockers (a class of Na V 1.7 antagonists used also in our study) administered systemically before histamine intradermal injection reduced scratching by up to 85% (Graceffa et al, 2017;Kornecook et al, 2017;La et al, 2017).…”

Section: Discussionmentioning

confidence: 68%

Voltage-Gated Sodium Channels Regulating Action Potential Generation in Itch-, Nociceptive-, and Low-Threshold Mechanosensitive Cutaneous C-Fibers

et al. 2018

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We evaluated the effect of voltage-gated sodium channel 1 (Na1) blockers in three nonoverlapping C-fiber subtypes in the mouse skin: chloroquine (CQ)-sensitive C-fibers with high mechanical thresholds- second, CQ-insensitive, capsaicin-sensitive C-fibers with high mechanical thresholds- and CQ and capsaicin-insensitive C-fibers with a very low mechanical threshold-C-LTMs. Na1-blocking drugs were applied to the nerve terminal receptive fields using an innervated isolated dorsal mouse skin-nerve preparation where the drugs are delivered into the skin intra-arterially. We combined these studies with an analysis of the mRNA expression of the -subunits of Na1 in individual dorsal root ganglia neurons labeled from the same region of the skin. Our results show that virtually all nociceptors and itch C-fibers expressed the tetrodotoxin (TTX)-resistant channels Na1.8 and Na1.9. However, TTX applied selectively into the skin abolished the action potential firing in response to mechanical stimulation in 75% of the itch C-fibers, 100% of the nociceptors, and 100% of C-LTMs. Na1.7 was the most commonly expressed TTX-sensitive Na1 in all three C-fiber subtypes innervating the dorsal skin. Selectively blocking Na1.7 abolished responses in about 40% of itch C-fibers, 65% of nociceptors, but only 20% of C-LTMs. Blocking Na1.8 alone had no affect on the firing sensitivity of the C-fibers. However, in itch and nociceptive C-fibers where the activation was not inhibited with a Na1.7 blocker, adding the Na1.8 blocker silenced action potential discharge.

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“…There is also considerable interest in various sulfonamide analogs which display selectivity toward Na v 1.7 and are effective in pain mitigation in animal models [ (178)(179)(180)(181)(182)(183); see Table 1]. Therapeutic concentrations of the inactivated state blocker PF-05089771 increase the rheobase of control neurons, but not that of Na v 1.7 knock-out neurons.…”

Section: Pharmacological Manipulation Of Na V 17mentioning

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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The discovery of benzoxazine sulfonamide inhibitors of Na V 1.7: Tools that bridge efficacy and target engagement

Cited by 18 publications

References 32 publications

Complementary roles of murine NaV1.7, NaV1.8 and NaV1.9 in acute itch signalling

Complementary roles of murine NaV1.7, NaV1.8 and NaV1.9 in acute itch signalling

Voltage-Gated Sodium Channels Regulating Action Potential Generation in Itch-, Nociceptive-, and Low-Threshold Mechanosensitive Cutaneous C-Fibers

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

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