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NaV 1.8 blocker

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https://www.readbyqxmd.com/read/27271997/t-boc-synthesis-of-huwentoxin-i-through-native-chemical-ligation-incorporating-a-trifluoromethanesulfonic-acid-cleavage-strategy
#1
Parashar Thapa, Chino C Cabalteja, Edwin E Philips, Michael J Espiritu, Steve Peigneur, Bea G Mille, Jan Tytgat, Theodore R Cummins, Jon-Paul Bingham
Tert-butyloxycarbonyl (t-Boc)-based native chemical ligation (NCL) techniques commonly employ hydrogen fluoride (HF) to create the thioester fragment required for the ligation process. Our research aimed to assess the replacement of HF with Trifluoromethanesulfonic acid (TFMSA). Here we examined a 33 amino acid test peptide, Huwentoxin-I (HwTx-I) as a novel candidate for our TFMSA cleavage protocol. Structurally HwTx-I has an X-Cys(16) -Cys(17) -X sequence mid-region, which makes it an ideal candidate for NCL...
September 2016: Biopolymers
https://www.readbyqxmd.com/read/26684879/dynamic-weight-bearing-as-a-non-reflexive-method-for-the-measurement-of-abdominal-pain-in-mice
#2
A Laux-Biehlmann, J Boyken, H Dahllöf, N Schmidt, T M Zollner, J Nagel
BACKGROUND: Chronic pelvic pain (CPP) is a high burden for patients and society. It affects 15-24% of women in reproductive age and is an area of high unmet medical need. CPP can be caused by a wide range of visceral diseases such as abdominal infections, gastrointestinal or gynaecological diseases like endometriosis. Despite the high medical need for this condition, pharmacological approaches are hampered by the limited number of available methods for the behavioural evaluation of pain in inflammation-driven animal models of pelvic pain...
May 2016: European Journal of Pain: EJP
https://www.readbyqxmd.com/read/25818052/osteoarthritis-dependent-changes-in-antinociceptive-action-of-nav1-7-and-nav1-8-sodium-channel-blockers-an-in-vivo-electrophysiological-study-in-the-rat
#3
W Rahman, A H Dickenson
Voltage-gated sodium channel blockers are not traditionally recommended for osteoarthritis (OA) pain therapy, but given the large peripheral drive that follows OA development there is a rationale for their use. Using a rat model of monosodium iodoacetate (MIA)-induced OA we used in vivo electrophysiology to assess the effects of the Nav1.7- and Nav1.8-selective antagonists, ProTxII and A-803467 respectively, on the evoked activity of spinal dorsal horn neurons in response to electrical, mechanical and thermal stimuli applied to the peripheral receptive field...
June 4, 2015: Neuroscience
https://www.readbyqxmd.com/read/25632083/%C3%AE-and-%C3%AE-subunit-composition-of-voltage-gated-sodium-channels-investigated-with-%C3%AE-conotoxins-and-the-recently-discovered-%C3%AE-o%C3%A2-conotoxin-gviij
#4
Michael J Wilson, Min-Min Zhang, Joanna Gajewiak, Layla Azam, Jean E Rivier, Baldomero M Olivera, Doju Yoshikami
We investigated the identities of the isoforms of the α (NaV1)- and β (NaVβ)-subunits of voltage-gated sodium channels, including those responsible for action potentials in rodent sciatic nerves. To examine α-subunits, we used seven μ-conotoxins, which target site 1 of the channel. With the use of exogenously expressed channels, we show that two of the μ-conotoxins, μ-BuIIIB and μ-SxIIIA, are 50-fold more potent in blocking NaV1.6 from mouse than that from rat. Furthermore, we observed that μ-BuIIIB and μ-SxIIIA are potent blockers of large, myelinated A-fiber compound action potentials (A-CAPs) [but not small, unmyelinated C-fiber CAPs (C-CAPs)] in the sciatic nerve of the mouse (unlike A-CAPs of the rat, previously shown to be insensitive to these toxins)...
April 1, 2015: Journal of Neurophysiology
https://www.readbyqxmd.com/read/25625641/a-novel-selective-and-orally-bioavailable-nav-1-8-channel-blocker-pf-01247324-attenuates-nociception-and-sensory-neuron-excitability
#5
Claire Elizabeth Payne, Adam R Brown, Jonathon W Theile, Alexandre J C Loucif, Aristos J Alexandrou, Mathew D Fuller, John H Mahoney, Brett M Antonio, Aaron C Gerlach, David M Printzenhoff, Rebecca L Prime, Gillian Stockbridge, Anthony J Kirkup, Anthony W Bannon, Steve England, Mark L Chapman, Sharan Bagal, Rosemarie Roeloffs, Uma Anand, Praveen Anand, Peter J Bungay, Mark Kemp, Richard P Butt, Edward B Stevens
BACKGROUND AND PURPOSE: NaV 1.8 ion channels have been highlighted as important molecular targets for the design of low MW blockers for the treatment of chronic pain. Here, we describe the effects of PF-01247324, a new generation, selective, orally bioavailable Nav 1.8 channel blocker of novel chemotype. EXPERIMENTAL APPROACH: The inhibition of Nav 1.8 channels by PF-01247324 was studied using in vitro patch-clamp electrophysiology and the oral bioavailability and antinociceptive effects demonstrated using in vivo rodent models of inflammatory and neuropathic pain...
May 2015: British Journal of Pharmacology
https://www.readbyqxmd.com/read/24903831/tetrodotoxin-resistant-voltage-gated-sodium-channel-nav-1-8-constitutively-interacts-with-ankyrin-g
#6
Audrey Montersino, Anna Brachet, Géraldine Ferracci, Marie-Pierre Fache, Stephanie Angles d'Ortoli, Wenjing Liu, Fanny Rueda-Boroni, Francis Castets, Bénédicte Dargent
The tetrodotoxin-resistant (TTX-R) voltage-gated sodium channel Nav 1.8 is predominantly expressed in peripheral afferent neurons, but in case of neuronal injury an ectopic and detrimental expression of Nav 1.8 occurs in neurons of the CNS. In CNS neurons, Nav 1.2 and Nav 1.6 channels accumulate at the axon initial segment, the site of the generation of the action potential, through a direct interaction with the scaffolding protein ankyrin G (ankG). This interaction is regulated by protein kinase CK2 phosphorylation...
October 2014: Journal of Neurochemistry
https://www.readbyqxmd.com/read/24755846/inhibition-of-voltage-gated-na%C3%A2-%C2%BA-channels-by-the-synthetic-cannabinoid-ajulemic-acid
#7
Nilufar Foadi, Christian Berger, Igor Pilawski, Carsten Stoetzer, Matthias Karst, Gertrud Haeseler, Florian Wegner, Andreas Leffler, Jörg Ahrens
BACKGROUND: The synthetic cannabinoid ajulemic acid has been demonstrated to alleviate pain in patients suffering from chronic neuropathic pain. Cannabinoids interact with several molecules within the pain circuit, including a potent inhibition of voltage-gated sodium channels. In this study, we closely characterized this property on neuronal and nonneuronal sodium channels. METHODS: The inhibition of sodium inward currents by ajulemic acid was studied in vitro...
June 2014: Anesthesia and Analgesia
https://www.readbyqxmd.com/read/24452459/diterpene-alkaloids-from-the-roots-of-aconitum-moldavicum-and-assessment-of-nav%C3%A2-1-2-sodium-channel-activity-of-aconitum-alkaloids
#8
Botond Borcsa, László Fodor, Dezső Csupor, Peter Forgo, Attila Molnár, Judit Hohmann
A new aconitane alkaloid, 1-O-demethylswatinine (1), was isolated from the root of Aconitum moldavicum together with the known compounds cammaconine (2), columbianine (3), swatinine (4), gigactonine (5), delcosine (6), lycoctonine (7), and ajacine (8). The structures were established by means of HRESIMS, 1D and 2D NMR spectroscopy, including 1H-1H COSY, NOESY, HSQC, and HMBC experiments, resulting in complete 1H-NMR chemical shift assignments for 1-4. The effects of the isolated compounds 4-8, together with eighteen other Aconitum diterpene and norditerpene alkaloids with different skeletal types and substitution patterns, were studied on Nav 1...
February 2014: Planta Medica
https://www.readbyqxmd.com/read/24272479/targeting-voltage-gated-sodium-channels-nav1-7-na-v1-8-and-na-v1-9-for-treatment-of-pathological-cough
#9
REVIEW
Yukiko Muroi, Bradley J Undem
Recent advances in our understanding of voltage-gated sodium channels (NaVs) lead to the rational hypothesis that drugs capable of selective blockade of NaV subtypes may be a safe and effective strategy for the treatment of unwanted cough. Among the nine NaV subtypes (NaV1.1-NaV1.9), the afferent nerves involved in initiating cough, in common with nociceptive neurons in the somatosensory system, express mainly NaV1.7, NaV1.8, and NaV1.9. Although knowledge about the effect of selectively blocking these channels on the cough reflex is limited, their biophysical properties indicate that each may contribute to the hypertussive and allotussive state that typifies subacute and chronic nonproductive cough...
February 2014: Lung
https://www.readbyqxmd.com/read/23778145/dysregulation-of-voltage-gated-sodium-channels-by-ubiquitin-ligase-nedd4-2-in-neuropathic-pain
#10
Cédric J Laedermann, Matthieu Cachemaille, Guylène Kirschmann, Marie Pertin, Romain-Daniel Gosselin, Isabelle Chang, Maxime Albesa, Chris Towne, Bernard L Schneider, Stephan Kellenberger, Hugues Abriel, Isabelle Decosterd
Peripheral neuropathic pain is a disabling condition resulting from nerve injury. It is characterized by the dysregulation of voltage-gated sodium channels (Navs) expressed in dorsal root ganglion (DRG) sensory neurons. The mechanisms underlying the altered expression of Na(v)s remain unknown. This study investigated the role of the E3 ubiquitin ligase NEDD4-2, which is known to ubiquitylate Navs, in the pathogenesis of neuropathic pain in mice. The spared nerve injury (SNI) model of traumatic nerve injury-induced neuropathic pain was used, and an Na(v)1...
July 2013: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/23685008/the-scorpion-toxin-amm-viii-induces-pain-hypersensitivity-through-gain-of-function-of-ttx-sensitive-na%C3%A2-%C2%BA-channels
#11
Najwa Abbas, Christelle Gaudioso-Tyzra, Caroline Bonnet, Mélanie Gabriac, Muriel Amsalem, Aurélie Lonigro, Françoise Padilla, Marcel Crest, Marie-France Martin-Eauclaire, Patrick Delmas
Voltage-gated Na(+) channels (Nav) are the targets of a variety of scorpion toxins. Here, we investigated the effects of Amm VIII, a toxin isolated from the venom of the scorpion Androctonus mauretanicus mauretanicus, on pain-related behaviours in mice. The effects of Amm VIII were compared with the classic scorpion α-toxin AaH II from Androctonus australis. Contrary to AaH II, intraplantar injection of Amm VIII at relatively high concentrations caused little nocifensive behaviours. However, Amm VIII induced rapid mechanical and thermal pain hypersensitivities...
August 2013: Pain
https://www.readbyqxmd.com/read/23523647/attenuation-of-autonomic-reflexes-by-a803467-may-not-be-solely-caused-by-blockade-of-nav-1-8-channels
#12
Audrey J Stone, Joyce S Kim, Katsuya Yamauchi, Victor Ruiz-Velasco, Marc P Kaufman
In decerebrated rats, we determined the dose of A803467, a NaV 1.8 antagonist, needed to attenuate the reflex pressor responses to femoral arterial injections of lactic acid (24 mM; ~0.1 ml) and capsaicin (0.1 μg), agents which stimulate thin fiber afferents having NaV 1.8 channels. We also determined whether the dose of A803467 needed to attenuate these reflex responses affected the responses of muscle spindle afferents to tendon stretch and succinylcholine (200 μg). Spindle afferents are not supplied with NaV 1...
May 24, 2013: Neuroscience Letters
https://www.readbyqxmd.com/read/23364266/effective-contractile-response-to-voltage-gated-na-channels-revealed-by-a-channel-activator
#13
W-S Vanessa Ho, Alison J Davis, Preet S Chadha, Iain A Greenwood
This study investigated the molecular identity and impact of enhancing voltage-gated Na(+) (Na(V)) channels in the control of vascular tone. In rat isolated mesenteric and femoral arteries mounted for isometric tension recording, the vascular actions of the Na(V) channel activator veratridine were examined. Na(V) channel expression was probed by molecular techniques and immunocytochemistry. In mesenteric arteries, veratridine induced potent contractions (pEC(50) = 5.19 ± 0.20, E(max) = 12.0 ± 2.7 mN), which were inhibited by 1 μM TTX (a blocker of all Na(V) channel isoforms, except Na(V)1...
April 15, 2013: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/23229998/analgesic-ineffectiveness-of-lacosamide-after-spinal-nerve-ligation-and-its-sodium-channel-activity-in-injured-neurons
#14
T Hagenacker, N Schäfer, D Büsselberg, M Schäfers
BACKGROUND: Lacosamide is a novel anti-epileptic drug that enhances the slow- and not fast-inactivating state of voltage-gated sodium channels. Lacosamide has demonstrated analgesic efficacy in several animal studies but preclinical studies on neuropathic pain models are rare, and recent clinical trials showed no superior analgesic effects. METHODS: Here, we examine whether an acute or chronic administration of lacosamide (3-60 mg/kg, i.p.) attenuates pain behaviour induced by spinal nerve ligation (SNL)...
July 2013: European Journal of Pain: EJP
https://www.readbyqxmd.com/read/23222359/the-%C3%AE%C2%BA-opioid-receptor-agonist-u-50488-blocks-ca2-channels-in-a-voltage-and-g-protein-independent-manner-in-sensory-neurons
#15
Bassil Hassan, Victor Ruiz-Velasco
BACKGROUND AND OBJECTIVES: κ-Opioid receptor (κ-OR) activation is known to play a role in analgesia and central sedation. The purpose of the present study was to examine the effect of the κ-OR agonist, U-50488 (an arylacetamide), on Ca channel currents and the signaling proteins involved in acutely isolated rat dorsal root ganglion (DRG) neurons expressing the putative promoter region of the tetrodotoxin-resistant Na channel (NaV 1.8) that is known to be involved in pain transmission...
January 2013: Regional Anesthesia and Pain Medicine
https://www.readbyqxmd.com/read/22225591/involvement-of-nav-1-8-sodium-ion-channels-in-the-transduction-of-mechanical-pain-in-a-rodent-model-of-osteoarthritis
#16
Niklas Schuelert, Jason J McDougall
INTRODUCTION: A subgroup of voltage gated sodium channels including Nav1.8 are exclusively expressed on small diameter primary afferent neurons and are therefore believed to be integral to the neurotransmission of nociceptive pain. The present study examined whether local application of A-803467, a selective blocker of the Nav 1.8 sodium channel, can reduce nociceptive transmission from the joint in a rodent model of osteoarthritis (OA). METHODS: OA-like changes were induced in male Wistar rats by an intra-articular injection of 3 mg sodium monoiodoacetate (MIA)...
2012: Arthritis Research & Therapy
https://www.readbyqxmd.com/read/21586605/nav%C3%AE-subunits-modulate-the-inhibition-of-nav1-8-by-the-analgesic-gating-modifier-%C3%AE-o-conotoxin-mrvib
#17
COMPARATIVE STUDY
Michael J Wilson, Min-Min Zhang, Layla Azam, Baldomero M Olivera, Grzegorz Bulaj, Doju Yoshikami
Voltage-gated sodium channels (VGSCs) consist of a pore-forming α-subunit and regulatory β-subunits. Several families of neuroactive peptides of Conus snails target VGSCs, including μO-conotoxins and μ-conotoxins. Unlike μ-conotoxins and the guanidinium alkaloid saxitoxin (STX), which are pore blockers, μO-conotoxins MrVIA and MrVIB inhibit VGSCs by modifying channel gating. μO-MrVIA/B can block Na(v)1.8 (a tetrodotoxin-resistant isoform of VGSCs) and have analgesic properties. The effect of Na(v)β-subunit coexpression on susceptibility to block by μO-MrVIA/B and STX has, until now, not been reported...
August 2011: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/19773645/ranolazine-attenuates-behavioral-signs-of-neuropathic-pain
#18
Harry J Gould, Colleen Garrett, Renee R Donahue, Dennis Paul, Ivan Diamond, Bradley K Taylor
Ranolazine modulates the cardiac voltage-gated sodium channel (NaV 1.5) and is approved by the FDA in the treatment of ischemic heart disease. Ranolazine also targets neuronal (NaV 1.7, 1.8) isoforms that are implicated in neuropathic pain. Therefore, we determined the analgesic efficacy of ranolazine in a preclinical animal model of neuropathic pain. Both intraperitoneal and oral administration of ranolazine dose-dependently inhibited the mechanical and cold allodynia associated with spared nerve injury, without producing ataxia or other behavioral side effects...
December 2009: Behavioural Pharmacology
https://www.readbyqxmd.com/read/19672182/isoflurane-inhibits-the-tetrodotoxin-resistant-voltage-gated-sodium-channel-nav1-8
#19
Karl F Herold, Carla Nau, Wei Ouyang, Hugh C Hemmings
BACKGROUND: Voltage-gated sodium channels (Nav) mediate neuronal action potentials. Tetrodotoxin inhibits all Nav isoforms, but Nav1.8 and Nav1.9 are relatively tetrodotoxin-resistant (TTX-r) compared to other isoforms. Nav1.8 is highly expressed in dorsal root ganglion neurons and is functionally linked to nociception, but the sensitivity of TTX-r isoforms to inhaled anesthetics is unclear. METHODS: The sensitivities of heterologously expressed rat TTX-r Nav1.8 and endogenous tetrodotoxin-sensitive (TTX-s) Nav to the prototypic inhaled anesthetic isoflurane were tested in mammalian ND7/23 cells using patch-clamp electrophysiology...
September 2009: Anesthesiology
https://www.readbyqxmd.com/read/18698149/muo-conotoxins-inhibit-nav-channels-by-interfering-with-their-voltage-sensors-in-domain-2
#20
Enrico Leipold, Herbert DeBie, Stefan Zorn, Adolfo Borges, Baldomero M Olivera, Heinrich Terlau, Stefan H Heinemann
The muO-conotoxins MrVIA and MrVIB are 31-residue peptides from Conus marmoreus, belonging to the O-superfamily of conotoxins with three disulfide bridges. They have attracted attention because they are inhibitors of tetrodotoxin-insensitive voltage-gated sodium channels (Na(V)1.8) and could therefore serve as lead structure for novel analgesics. The aim of this study was to elucidate the molecular mechanism by which muO-conotoxins affect Na(V) channels. Rat Na(V)1.4 channels and mutants thereof were expressed in mammalian cells and were assayed with the whole-cell patch-clamp method...
July 2007: Channels
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