Last update 01 Nov 2024

Nav1.8 x Nav1.6 x Nav1.7

Last update 01 Nov 2024

Basic Info

Related Targets

Nav1.8Nav1.6Nav1.7

Drugs associated with Nav1.8 x Nav1.6 x Nav1.7

BL-1021

Target

Nav1.6 x Nav1.7 x Nav1.8

Mechanism

Nav1.6 blockers [+2]

Active Org.-

Originator Org.

Bar-Ilan University

Active Indication-

Inactive Indication

Neuralgia

Drug Highest PhaseDiscontinued

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with Nav1.8 x Nav1.6 x Nav1.7

NCT01121380 / TerminatedPhase 1

A First-in-Human, Randomized, Double-Blind, Placebo Controlled, Single-Center Combined Single-Ascending Dose and Multiple-Ascending Dose, Parallel Groups, Study to Assess Safety, Tolerability and Pharmacokinetics of BL-1021 in Healthy Volunteers

The purpose of this study is to test the safety, tolerability and pharmacokinetics of BL-1021 in healthy volunteers. Subsequent clinical studies will be designed to test the safety and efficacy of BL-1021 in patients with neuropathic pain based on data obtained from the proposal trial described below.

Start Date01 Jun 2011

Sponsor / Collaborator

BioLineRx Ltd.

100 Clinical Results associated with Nav1.8 x Nav1.6 x Nav1.7

100 Translational Medicine associated with Nav1.8 x Nav1.6 x Nav1.7

0 Patents (Medical) associated with Nav1.8 x Nav1.6 x Nav1.7

Literatures (Medical) associated with Nav1.8 x Nav1.6 x Nav1.7

20 Mar 2024·ACS Chemical Neuroscience

Nav1.7 Modulator Bearing a 3-Hydroxyindole Backbone Holds the Potential to Reverse Neuropathic Pain

Article

Author: Shu, Jirong ; Shan, Zhiming ; Cai, Song ; Hong, Kemiao ; Yang, Haoyi ; Liu, Tao ; Li, Fuyi ; Guo, Weijie ; Shi, Taoda ; Zhang, Jian ; Yang, Xiangji ; Wang, Yuwei ; Fang, Jie

Chronic pain is a growing global health problem affecting at least 10% of the world's population. However, current chronic pain treatments are inadequate. Voltage-gated sodium channels (Navs) play a pivotal role in regulating neuronal excitability and pain signal transmission and thus are main targets for nonopioid painkiller development, especially those preferentially expressed in dorsal root ganglial (DRG) neurons, such as Nav1.6, Nav1.7, and Nav1.8. In this study, we screened in virtual hits from dihydrobenzofuran and 3-hydroxyoxindole hybrid molecules against Navs via a veratridine (VTD)-based calcium imaging method. The results showed that one of the molecules, 3g, could inhibit VTD-induced neuronal activity significantly. Voltage clamp recordings demonstrated that 3g inhibited the total Na⁺ currents of DRG neurons in a concentration-dependent manner. Biophysical analysis revealed that 3g slowed the activation, meanwhile enhancing the inactivation of the Navs. Additionally, 3g use-dependently blocked Na⁺ currents. By combining with selective Nav inhibitors and a heterozygous expression system, we demonstrated that 3g preferentially inhibited the TTX-S Na⁺ currents, specifically the Nav1.7 current, other than the TTX-R Na⁺ currents. Molecular docking experiments implicated that 3g binds to a known allosteric site at the voltage-sensing domain IV(VSDIV) of Nav1.7. Finally, intrathecal injection of 3g significantly relieved mechanical pain behavior in the spared nerve injury (SNI) rat model, suggesting that 3g is a promising candidate for treating chronic pain.

01 Apr 2021·PainQ1 · MEDICINE

Antinociceptive properties of an isoform-selective inhibitor of Nav1.7 derived from saxitoxin in mouse models of pain

Q1 · MEDICINE

Article

Author: Giuvelis, Denise ; Meng, Ian D. ; Mulcahy, John V. ; Hunter, John C. ; Zhou, Xiang ; Beckley, Jacob T. ; Klas, Sheri ; Monteleone, Dennis ; Yeomans, David C. ; Luu, George ; Pajouhesh, Hassan ; Delwig, Anton

AbstractThe voltage-gated sodium channel Nav1.7 is highly expressed in nociceptive afferents and is critically involved in pain signal transmission. Nav1.7 is a genetically validated pain target in humans because loss-of-function mutations cause congenital insensitivity to pain and gain-of-function mutations cause severe pain syndromes. Consequently, pharmacological inhibition has been investigated as an analgesic therapeutic strategy. We describe a small molecule Nav1.7 inhibitor, ST-2530, that is an analog of the naturally occurring sodium channel blocker saxitoxin. When evaluated against human Nav1.7 by patch-clamp electrophysiology using a protocol that favors the resting state, the Kd of ST-2530 was 25 ± 7 nM. ST-2530 exhibited greater than 500-fold selectivity over human voltage-gated sodium channel isoforms Nav1.1–Nav1.6 and Nav1.8. Although ST-2530 had lower affinity against mouse Nav1.7 (Kd = 250 ± 40 nM), potency was sufficient to assess analgesic efficacy in mouse pain models. A 3-mg/kg dose administered subcutaneously was broadly analgesic in acute pain models using noxious thermal, mechanical, and chemical stimuli. ST-2530 also reversed thermal hypersensitivity after a surgical incision on the plantar surface of the hind paw. In the spared nerve injury model of neuropathic pain, ST-2530 transiently reversed mechanical allodynia. These analgesic effects were demonstrated at doses that did not affect locomotion, motor coordination, or olfaction. Collectively, results from this study indicate that pharmacological inhibition of Nav1.7 by a small molecule agent with affinity for the resting state of the channel is sufficient to produce analgesia in a range of preclinical pain models.

01 Jan 2021·Molecular PainQ3 · MEDICINE

Trigeminal neuralgia and genetics: A systematic review

Q3 · MEDICINE

ReviewOA

Author: Mannerak, Mari Aaroe ; Lashkarivand, Aslan ; Eide, Per Kristian

Trigeminal neuralgia (TN) is a severe facial pain disease of unknown cause and unclear genetic background. To examine the existing knowledge about genetics in TN, we performed a systematic study asking about the prevalence of familial trigeminal neuralgia, and which genes that have been identified in human TN studies and in animal models of trigeminal pain. MedLine, Embase, Cochrane Library and Web of Science were searched from inception to January 2021. 71 studies were included in the systematic review. Currently, few studies provide information about the prevalence of familial TN; the available evidence indicates that about 1–2% of TN cases have the familial form. The available human studies propose the following genes to be possible contributors to development of TN: CACNA1A, CACNA1H, CACNA1F, KCNK1, TRAK1, SCN9A, SCN8A, SCN3A, SCN10A, SCN5A, NTRK1, GABRG1, MPZ gene, MAOA gene and SLC6A4. Their role in familial TN still needs to be addressed. The experimental animal studies suggest an emerging role of genetics in trigeminal pain, though the animal models may be more relevant for trigeminal neuropathic pain than TN per se. In summary, this systematic review suggests a more important role of genetic factors in TN pathogenesis than previously assumed.

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