Sodium Channel Inhibitor

Fluphenazine dihydrochloride is a potent, orally active phenothiazine-based dopamine receptor antagonist. Fluphenazine dihydrochloride blocks neuronal voltage-gated sodium channels. Fluphenazine dihydrochloride acts primarily through antagonism of postsynaptic dopamine-2 receptors in mesolimbic, nigrostriatal, and tuberoinfundibular neural pathways. Fluphenazine dihydrochloride can antagonize Methylphenidate-induced stereotyped gnawing and inhibit climbing behaviour in mice. Fluphenazine dihydrochloride can be used for researching psychosis and painful peripheral neuropathy associated with diabetes and has potential to inhibit SARS-CoV-2.

Ranolazine (CVT 303) is an anti-angina drug that achieves its effects by inhibiting the late phase of inward sodium current (I_Na and I_Kr with IC₅₀ values of 6 μM and 12 μM, respectively) without affecting heart rate or blood pressure (BP). Ranolazine is also a partial fatty acid oxidation (FAO) inhibitor. Antianginal agent.

Triamterene blocks epithelial Na⁺ channel (ENaC) in a voltage-dependent manner, which used as a mild diuretic. Triamterene is an inhibitor of the TGR5 receptor.

Amitriptyline hydrochloride is an orally active tricyclic antidepressant (TCA). Amitriptyline hydrochloride mainly exerts its antidepressant effect by blocking SERT (K_i = 3.45 nM) and NET (K_i = 13.3 nM), thereby increasing the concentrations of 5-hydroxytryptamine (5-HT) and norepinephrine (NE) in the synaptic cleft. Amitriptyline hydrochloride is also an agonist at α2A and TrkA/TrkB receptors, thereby exerting analgesic and neurotrophic activities (inhibiting cell apoptosis). Amitriptyline hydrochloride can reduce inflammation, angiogenesis and fibrosis. Amitriptyline hydrochloride binds to DAT (with K_i = 2.58 μM). Amitriptyline hydrochloride has high affinity for a series of receptors and can antagonize muscarinic cholinergic receptors (M1/M2/M3/M4/M5 receptors) (K_i = 11-24 nM), H1 receptors (K_i = 0.5-1.1 nM), adrenergic α1 receptors (K_i = 4.4 nM), etc., resulting in a series of side effects. Amitriptyline hydrochloride can block sodium channels and hERG potassium channel (IC₅₀ = 4.78 μM) and it has cardiotoxicity.

Primidone is the orally active inhibitor for TRPM3 (IC₅₀ = 0.6 μM), RIP kinase and voltage-gated sodium channel, and the antagonist for GABA receptor. Primidone can be used as the analgesic and anticonvulsant agent.

DSP-2230 is the orally active inhibitor for voltage-gated sodium channel that inhibits Nav1.7-, Nav1.8-, and Nav1.9-derived sodium currents with IC₅₀s of 7.1 μM, 11.4 μM and 6.7 μM, respectively. DSP-2230 can be used to improve neuropathic pain.

Atomoxetine (Tomoxetine) hydrochloride is a selective noradrenaline reuptake inhibitor with K_i values of 5 nM, 77 nM and 1451 nM for norepinephrine (NE), serotonin (5-HT) and dopamine (DA) transporters, respectively. Atomoxetine hydrochloride is a potent Na⁺ channels (VGSCs) blocker. Atomoxetine hydrochloride can be used for attention-deficit hyperactivity disorder (ADHD) research.

Mexiletine is an orally effective antiarrhythmic agent which has also been found to be effective for myotonia and neuropathic pain. Mexiletine exerts its efficacy through blocking sodium channels (IC₅₀ : 75±8 μM for tonic block, 23.6±2.8 μM for use-dependent block), therefore can be used for cardiovascular and neurological research.

5-(N,N-Hexamethylene)-amiloride (Hexamethylene amiloride) derives from an amiloride and is a potent Na⁺/H⁺ exchanger inhibitor, which decreases the intracellular pH (pH_i) and induces apoptosis in leukemic cells. 5-(N,N-Hexamethylene)-amiloride (Hexamethylene amiloride) is also an inhibitor of the HIV-1 Vpu virus ion channel and inhibits mouse hepatitis virus (MHV) replication and human coronavirus 229E (HCoV229E) replication in cultured L929 cells with EC₅₀s of 3.91 μM and 1.34 μM, respectively.

Zandatrigine (NBI-921352; XEN901) is a selective, orally active, voltage-gated sodium channel Na_V1.6/SCN8A inhibitor that can penetrate the blood-brain barrier. Zandatrigine inhibits sodium influx by non-covalently binding to the VSD4 structure of Na_V1.6, blocking the persistent and resuscitative currents under pathological conditions. Zandatrigine can reduce neuronal hyperexcitability and reduce epileptic seizures. Zandatrigine is 134-756-fold selective for other isoforms such as Na_V1.1 and Na_V1.2, and has minimal effect on Na_V1.1 expressed by inhibitory interneurons. Zandatrigine can be used to study Na_V1.6-mediated neuroexcitability diseases such as SCN8A-related developmental epileptic encephalopathy (SCN8A-DEE) and adult focal epilepsy.

Flecainide acetate (R-818) is a class 1C antiarrhythmic agent especially used for the management of supraventricular arrhythmia; works by blocking the Nav1.5 sodium channel in the heart, causing prolongation of the cardiac action potential.

Rufinamide (CGP 33101) is an orally active antiepileptic compound that inhibits Na⁺ current activation, inhibits neuronal hyperexcitability, and has anticonvulsant effects. Rufinamide is used in the study of Lennox-Gastaut syndrome.

ICA-121431 is a nanomolar potent and broad-spectrum voltage-gated sodium channel (Na_v) blocker, shows equipotent selectivity for human Na_v1.1 and Na_v1.3 subtypes with IC₅₀ values of 13 nM and 23 nM, respectively. ICA-121431 shows less potent inhibition of Na_v1.2 (IC₅₀=240 nM) and 1,000 fold selectivity against Na_v1.4, Na_v1.6, and the TTX-resistant human Na_v1.5 and Na_v1.8 channels (IC₅₀s >10 μM).

Quinacrine (Acriquine) is an antimalarial and anti-cancer agent. Quinacrine also inhibits human aldehyde oxidase (IC₅₀: 3.3 μM). Quinacrine has affinity for nucleic acids, and stains DNA and RNA in fixed cells (Ex/Em: 436/525 nm).

Riluzole hydrochloride is an anticonvulsant agent and belongs to the family of use-dependent Na⁺ channel blocker which can also inhibit GABA uptake with an IC₅₀ of 43 μM.

Ranolazine dihydrochloride (CVT 303 dihydrochloride) is an anti-angina agent that achieves its effects by inhibiting the late phase of inward sodium current (I_Na and I_Kr with IC₅₀ values of 6 μM and 12 μM, respectively) without affecting heart rate or blood pressure (BP). Ranolazine dihydrochloride is also a partial fatty acid oxidation inhibitor.

Propylparaben (Propyl parahydroxybenzoate) is an antibacterial preservative that can be produced by plants and bacteria. Propylparaben is an orally active weak estrogen receptor agonist. Propylparaben regulates the PI3K-AKT and JNK signaling pathways, and induces oxidative stress. Propylparaben is commonly used in cosmetics, pharmaceuticals and foods, and can be used in studies related to ovarian aging and myocardial ischemia-reperfusion injury.

Benzamil hydrochloride (Benzylamiloride hydrochloride), an Amiloride analogue, is a Na⁺/Ca²⁺ exchanger (NCX) inhibitor (IC₅₀~100 nM). Benzamil hydrochloride also is a non-selective Deg/epithelial sodium channels (ENaC) blocker, and can potentiate myogenic vasoconstriction. Benzamil hydrochloride inhibits TRPP3-mediated Ca²⁺-activated currents, with an IC₅₀ of 1.1 μM.

Bupivacaine hydrochloride is a NMDA receptor inhibitor.Bupivacaine can block sodium, L-calcium, and potassium channels.Bupivacaine potently blocks SCN5A channels with the IC₅₀ of 69.5 μM. Bupivacaine hydrochloride can be used for the research of chronic pain.

Phenytoin sodium (5,5-Diphenylhydantoin sodium salt) is a potent Voltage-gated Na⁺ channels (VGSCs) blocker. Phenytoin has antiepileptic activity and reduces breast tumour growth and metastasis in mice.