Na_v1.6 Inhibitor

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.

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).

PF-06456384 trihydrochloride is an extremely potent and selective Na_v1.7 sodium channel blocker (IC₅₀: 0.01 nM for hNaV1.7; 75 nM for rNaV1.7; <0.1 nM for mNaV1.7). PF-06456384 trihydrochloride shows no significant analgesic efficacy in the mouse Formalin pain model.

XPC-5462 is a selective Na_V1.6/1.2 inhibitor, with an IC₅₀ of 0.0103 μM against hNa_V1.6, 0.0137 μM against mNa_V1.6, and 0.0109 μM against hNa_V1.2. XPC-5462 significantly reduces epileptiform discharges. XPC-5462 is applicable for epilepsy-related research.

GDC-0310 is a selective acyl-sulfonamide Na_v1.7 inhibitor, with an IC₅₀ of 0.6 nM for hNa_v1.7.

XPC-7724 is a selective Na_v1.6 channel inhibitor with a IC₅₀ value of 0.078 μM. XPC-7724 can be used in the study of neurological diseases.

Funapide (TV 45070; XEN402) is an orally active inhibitor of voltage-gated sodium channels (VGSC) in the peripheral nervous system with IC₅₀ values ??of 84 nM and 54 nM for Nav1.5 and Nav1.7, respectively. Funapide has analgesic effects.

NaV1.2/1.6 channel blocker-1 is a potent NaV1.2/1.6 channel blocker, with IC₅₀s of 9.8 and 24.4 μM for rNaV1.6 and hNaV1.2, respectively. NaV1.2/1.6 channel blocker-1 can be used for the research of generalized epilepsy.

AA43279 is an in gamma-aminobutyric acid (GABA) fast-firing interneurons located activator for Nav1.1 channel (SCN1A) with an EC₅₀ of 9.5 μM. AA43279 enhances specific neuronal firing activity in vitro, and exhibits anticonvulsant activity in rat MEST model.

XPC-6444 is a highly potent, isoform-selective, and CNS-penetrant Na_V1.6 inhibitor (IC₅₀=41 nM for hNa_V1.6). XPC-6444 also displays potent block of Na_V1.2 (IC₅₀=125 nM). XPC-6444 shows anticonvulsant activity.

ProTx-I is a toxin derived from Thrixopelma pruriens and a peptide inhibitor targeting TTX-resistant sodium channels. ProTx-I interacts with voltage sensors of multiple domains such as NaV1.7, reduces neuronal excitability through allosteric modulation of channel gating and alteration of voltage dependence. The IC₅₀ values of ProTx-I against human NaV1.7, NaV1.2, NaV1.6, and NaV1.5 are 95 nM, 104 nM, 21 nM, and 358 nM, respectively; ProTx-I also potently inhibits Ba²⁺ currents of hCav3.1, while its inhibitory potency against hCav3.2 is approximately 160-fold lower. ProTx-I is applicable to the research of chronic pain.