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Nav1.7 AND small molecules

Rhiannon Thomas-Tran, J Du Bois
Improper function of voltage-gated sodium channels (NaVs), obligatory membrane proteins for bioelectrical signaling, has been linked to a number of human pathologies. Small-molecule agents that target NaVs hold considerable promise for treatment of chronic disease. Absent a comprehensive understanding of channel structure, the challenge of designing selective agents to modulate the activity of NaV subtypes is formidable. We have endeavored to gain insight into the 3D architecture of the outer vestibule of NaV through a systematic structure-activity relationship (SAR) study involving the bis-guanidinium toxin saxitoxin (STX), modified saxitoxins, and protein mutagenesis...
May 24, 2016: Proceedings of the National Academy of Sciences of the United States of America
Aristos J Alexandrou, Adam R Brown, Mark L Chapman, Mark Estacion, Jamie Turner, Malgorzata A Mis, Anna Wilbrey, Elizabeth C Payne, Alex Gutteridge, Peter J Cox, Rachel Doyle, David Printzenhoff, Zhixin Lin, Brian E Marron, Christopher West, Nigel A Swain, R Ian Storer, Paul A Stupple, Neil A Castle, James A Hounshell, Mirko Rivara, Andrew Randall, Sulayman D Dib-Hajj, Douglas Krafte, Stephen G Waxman, Manoj K Patel, Richard P Butt, Edward B Stevens
Human genetic studies show that the voltage gated sodium channel 1.7 (Nav1.7) is a key molecular determinant of pain sensation. However, defining the Nav1.7 contribution to nociceptive signalling has been hampered by a lack of selective inhibitors. Here we report two potent and selective arylsulfonamide Nav1.7 inhibitors; PF-05198007 and PF-05089771, which we have used to directly interrogate Nav1.7's role in nociceptor physiology. We report that Nav1.7 is the predominant functional TTX-sensitive Nav in mouse and human nociceptors and contributes to the initiation and the upstroke phase of the nociceptor action potential...
2016: PloS One
Marc Rogers, Nace Zidar, Danijel Kikelj, Robert W Kirby
The rodent neuroblastoma cell line, ND7-23, is used to express voltage-dependent sodium (Nav) and other neuronal ion channels resistant to heterologous expression in Chinese hamster ovary (CHO) or human embryonic kidney (HEK) cells. Their advantage is that they provide endogenous factors and signaling pathways to promote ion channel peptide folding, expression, and function at the cell surface and are also amenable to automated patch clamping. However, ND7-23 cells exhibit endogenous tetrodotoxin (TTX)-sensitive Nav currents, and molecular profiling has revealed the presence of Nav1...
March 2016: Assay and Drug Development Technologies
Wei-Chun J Hsu, Federico Scala, Miroslav N Nenov, Norelle C Wildburger, Hannah Elferink, Aditya K Singh, Charles B Chesson, Tetyana Buzhdygan, Maveen Sohail, Alexander S Shavkunov, Neli I Panova, Carol L Nilsson, Jai S Rudra, Cheryl F Lichti, Fernanda Laezza
Recent data shows that fibroblast growth factor 14 (FGF14) binds to and controls the function of the voltage-gated sodium (Nav) channel with phenotypic outcomes on neuronal excitability. Mutations in the FGF14 gene in humans have been associated with brain disorders that are partially recapitulated in Fgf14(-/-) mice. Thus, signaling pathways that modulate the FGF14:Nav channel interaction may be important therapeutic targets. Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1...
June 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Shivani Ahuja, Susmith Mukund, Lunbin Deng, Kuldip Khakh, Elaine Chang, Hoangdung Ho, Stephanie Shriver, Clint Young, Sophia Lin, J P Johnson, Ping Wu, Jun Li, Mary Coons, Christine Tam, Bobby Brillantes, Honorio Sampang, Kyle Mortara, Krista K Bowman, Kevin R Clark, Alberto Estevez, Zhiwei Xie, Henry Verschoof, Michael Grimwood, Christoph Dehnhardt, Jean-Christophe Andrez, Thilo Focken, Daniel P Sutherlin, Brian S Safina, Melissa A Starovasnik, Daniel F Ortwine, Yvonne Franke, Charles J Cohen, David H Hackos, Christopher M Koth, Jian Payandeh
Voltage-gated sodium (Nav) channels propagate action potentials in excitable cells. Accordingly, Nav channels are therapeutic targets for many cardiovascular and neurological disorders. Selective inhibitors have been challenging to design because the nine mammalian Nav channel isoforms share high sequence identity and remain recalcitrant to high-resolution structural studies. Targeting the human Nav1.7 channel involved in pain perception, we present a protein-engineering strategy that has allowed us to determine crystal structures of a novel receptor site in complex with isoform-selective antagonists...
December 18, 2015: Science
Cedric J Laedermann, Hugues Abriel, Isabelle Decosterd
In the peripheral sensory nervous system the neuronal expression of voltage-gated sodium channels (Navs) is very important for the transmission of nociceptive information since they give rise to the upstroke of the action potential (AP). Navs are composed of nine different isoforms with distinct biophysical properties. Studying the mutations associated with the increase or absence of pain sensitivity in humans, as well as other expression studies, have highlighted Nav1.7, Nav1.8, and Nav1.9 as being the most important contributors to the control of nociceptive neuronal electrogenesis...
2015: Frontiers in Pharmacology
Jennifer R Deuis, Ella Whately, Andreas Brust, Marco C Inserra, Naghmeh H Asvadi, Richard J Lewis, Paul F Alewood, Peter J Cabot, Irina Vetter
Selective activation of peripheral κ opioid receptors (KORs) may overcome the dose-limiting adverse effects of conventional opioid analgesics. We recently developed a vicinal disulfide-stabilized class of peptides with subnanomolar potency at the KOR. The aim of this study was to assess the analgesic effects of one of these peptides, named conorphin-1, in comparison with the prototypical KOR-selective small molecule agonist U-50488, in several rodent pain models. Surprisingly, neither conorphin-1 nor U-50488 were analgesic when delivered peripherally by intraplantar injection at local concentrations expected to fully activate the KOR at cutaneous nerve endings...
October 21, 2015: ACS Chemical Neuroscience
Justin K Murray, Kaustav Biswas, J Ryan Holder, Anruo Zou, Joseph Ligutti, Dong Liu, Leszek Poppe, Kristin L Andrews, Fen-Fen Lin, Shi-Yuan Meng, Bryan D Moyer, Stefan I McDonough, Les P Miranda
Many efforts are underway to develop selective inhibitors of the voltage-gated sodium channel NaV1.7 as new analgesics. Thus far, however, in vitro selectivity has proved difficult for small molecules, and peptides generally lack appropriate pharmacokinetic properties. We previously identified the NaV1.7 inhibitory peptide GpTx-1 from tarantula venom and optimized its potency and selectivity via structure-guided analoging. To further understand GpTx-1 binding to NaV1.7, we have mapped the binding site to transmembrane segments 1-4 of the second pseudosubunit internal repeat (commonly referred to as Site 4) using NaV1...
November 1, 2015: Bioorganic & Medicinal Chemistry Letters
Manuel de Lera Ruiz, Richard L Kraus
The tremendous therapeutic potential of voltage-gated sodium channels (Na(v)s) has been the subject of many studies in the past and is of intense interest today. Na(v)1.7 channels in particular have received much attention recently because of strong genetic validation of their involvement in nociception. Here we summarize the current status of research in the Na(v) field and present the most relevant recent developments with respect to the molecular structure, general physiology, and pharmacology of distinct Na(v) channel subtypes...
September 24, 2015: Journal of Medicinal Chemistry
Yu Du, Emily Days, Ian Romaine, Kris K Abney, Kristian Kaufmann, Gary Sulikowski, Shaun Stauffer, Craig W Lindsley, C David Weaver
Ion channels are critical for life, and they are targets of numerous drugs. The sequencing of the human genome has revealed the existence of hundreds of different ion channel subunits capable of forming thousands of ion channels. In the face of this diversity, we only have a few selective small-molecule tools to aid in our understanding of the role specific ion channels in physiology which may in turn help illuminate their therapeutic potential. Although the advent of automated electrophysiology has increased the rate at which we can screen for and characterize ion channel modulators, the technique's high per-measurement cost and moderate throughput compared to other high-throughput screening approaches limit its utility for large-scale high-throughput screening...
June 17, 2015: ACS Chemical Neuroscience
Shaoyi Sun, Charles J Cohen, Christoph M Dehnhardt
There has been intense interest in developing inhibitors of the sodium channel Nav1.7 because genetic studies have established very strong validation for the efficacy to alleviate both inflammatory and neuropathic pain. This review summarizes patent applications targeting Nav1.7 since 2010 until May, 2014. We have classified the patents into three categories as follows: small molecules with well-defined molecular selectivity among sodium channel isoforms; biologicals with well-defined molecular selectivity; and, small molecules that inhibit Nav1...
September 2014: Pharmaceutical Patent Analyst
Jun-Ho Lee, Chul-Kyu Park, Gang Chen, Qingjian Han, Rou-Gang Xie, Tong Liu, Ru-Rong Ji, Seok-Yong Lee
Voltage-gated sodium (NaV) channels control the upstroke of the action potentials in excitable cells. Multiple studies have shown distinct roles of NaV channel subtypes in human physiology and diseases, but subtype-specific therapeutics are lacking and the current efforts have been limited to small molecules. Here, we present a monoclonal antibody that targets the voltage-sensor paddle of NaV1.7, the subtype critical for pain sensation. This antibody not only inhibits NaV1.7 with high selectivity, but also effectively suppresses inflammatory and neuropathic pain in mice...
June 5, 2014: Cell
Ken McCormack, Sonia Santos, Mark L Chapman, Douglas S Krafte, Brian E Marron, Christopher W West, Michael J Krambis, Brett M Antonio, Shannon G Zellmer, David Printzenhoff, Karen M Padilla, Zhixin Lin, P Kay Wagoner, Nigel A Swain, Paul A Stupple, Marcel de Groot, Richard P Butt, Neil A Castle
Voltage-gated sodium (Nav) channels play a fundamental role in the generation and propagation of electrical impulses in excitable cells. Here we describe two unique structurally related nanomolar potent small molecule Nav channel inhibitors that exhibit up to 1,000-fold selectivity for human Nav1.3/Nav1.1 (ICA-121431, IC50, 19 nM) or Nav1.7 (PF-04856264, IC50, 28 nM) vs. other TTX-sensitive or resistant (i.e., Nav1.5) sodium channels. Using both chimeras and single point mutations, we demonstrate that this unique class of sodium channel inhibitor interacts with the S1-S4 voltage sensor segment of homologous Domain 4...
July 16, 2013: Proceedings of the National Academy of Sciences of the United States of America
Sulayman D Dib-Hajj, Yang Yang, Joel A Black, Stephen G Waxman
The voltage-gated sodium channel Na(V)1.7 is preferentially expressed in peripheral somatic and visceral sensory neurons, olfactory sensory neurons and sympathetic ganglion neurons. Na(V)1.7 accumulates at nerve fibre endings and amplifies small subthreshold depolarizations, poising it to act as a threshold channel that regulates excitability. Genetic and functional studies have added to the evidence that Na(V)1.7 is a major contributor to pain signalling in humans, and homology modelling based on crystal structures of ion channels suggests an atomic-level structural basis for the altered gating of mutant Na(V)1...
January 2013: Nature Reviews. Neuroscience
Sebastian Heinzmann, Stephen B McMahon
PURPOSE OF REVIEW: To inform on preclinical and early clinical advances in the effort to identify novel classes of analgesic drugs. RECENT FINDINGS: Human genetic and animal preclinical studies have identified several mechanisms that appear to make important contributions to abnormal pain states. From human genetics, a small number of patients with mutations in the genes encoding nerve growth factor/TrkA signaling and in a particular sodium channel subunit (SCN9a, encoding Nav1...
June 2011: Current Opinion in Supportive and Palliative Care
William A Schmalhofer, Kevin S Ratliff, Adam Weinglass, Gregory J Kaczorowski, Maria L Garcia, James Herrington
Gating modifier peptides alter gating of voltage-gated potassium (KV) channels by binding to the voltage sensor paddle and changing the energetics of channel opening. Since the voltage sensor paddle is a modular motif with low sequence similarity across families, targeting of this region should yield highly specific channel modifiers. To test this idea, we developed a binding assay with the KV2.1 gating modifier, GxTX-1E. Monoiodotyrosine-GxTX-1E (125I-GxTX-1E) binds with high affinity (IC50 = 4 nM) to CHO cells stably expressing hKV2...
November 2009: Channels
Cojen Ho, Michael E O'Leary
Sensory neurons of the dorsal root ganglia (DRG) express multiple voltage-gated sodium (Na) channels that substantially differ in gating kinetics and pharmacology. Small-diameter (<25 μm) neurons isolated from the rat DRG express a combination of fast tetrodotoxin-sensitive (TTX-S) and slow TTX-resistant (TTX-R) Na currents while large-diameter neurons (>30 μm) predominately express fast TTX-S Na current. Na channel expression was further investigated using single-cell RT-PCR to measure the transcripts present in individually harvested DRG neurons...
January 2011: Molecular and Cellular Neurosciences
Guillaume Barbara, Abdelkrim Alloui, Joël Nargeot, Philippe Lory, Alain Eschalier, Emmanuel Bourinet, Jean Chemin
Lipoamino acids are anandamide-related endogenous molecules that induce analgesia via unresolved mechanisms. Here, we provide evidence that the T-type/Cav3 calcium channels are important pharmacological targets underlying their physiological effects. Various lipoamino acids, including N-arachidonoyl glycine (NAGly), reversibly inhibited Cav3.1, Cav3.2, and Cav3.3 currents, with potent effects on Cav3.2 [EC(50) approximately 200 nm for N-arachidonoyl 3-OH-gamma-aminobutyric acid (NAGABA-OH)]. This inhibition involved a large shift in the Cav3...
October 21, 2009: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Rustem Onkal, Mustafa B A Djamgoz
A variety of ion channels have been detected in cancer cells. In particular, upregulation of voltage-gated sodium channels (VGSCs) has been associated pathophysiologically with several strongly metastatic carcinomas. This review emphasises breast cancer. Inhibiting VGSC activity in a number of independent ways, using the highly selective tetrodotoxin (TTX), gene silencing and a blocking polyclonal antibody, suppressed a range of cellular behaviors, especially directional motility and invasion, integral to the metastatic cascade...
December 25, 2009: European Journal of Pharmacology
Birgit T Priest
Voltage-gated sodium (NaV1) channels in the peripheral nervous system and CNS play a critical role in pain signaling. Nociceptive neurons express several NaV1 channel subtypes that may contribute to the hyperexcitability characteristic of chronic pain states. The non-subtype selective, state-dependent NaV1 channel blockers lidocaine and carbamazepine are efficacious in the treatment of neuropathic pain; however, the target-driven development of novel sodium channel blocking analgesics has been generally unsuccessful...
September 2009: Current Opinion in Drug Discovery & Development
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