The sodium channel is a complete membrane protein that forms the ion channel and transmits sodium ions (Na⁺) through the cell membrane. Besides, the sodium channel includes four similar domains. Each of them contains a highly charged S4 helix, which is driven (activated) outward in response to depolarization. In terms of function, the channel has two gates, called the activation gate and the deactivation gate. Moreover, Gate I is composed of inactivated “particles” in the cytoplasm and receptors in the channel. Mutations in the Nav channel can lead to neurological and cardiovascular diseases, making the channel an important therapeutic target.

Furthermore, a voltage-gated sodium channel (VGSC) is a transmembrane protein, whose function is similar to that of the gate controlling the ion flux across the cell membrane. Meanwhile, they are the key ion channels in excitable tissues that produce action potentials and have important physiological functions. Nonetheless, the abnormal function of VGSCs will lead to dysfunction of the body and lead to a variety of diseases. Here, we will introduce an orally active inhibitor of the persistent sodium channel, Relutrigine.

Relutrigine (PRAX-562) is an Orally Active Persistent Sodium Channel Inhibitor.

Above all, Relutrigine (PRAX-562) potently and preferentially inhibits persistent I_Na induced by ATX-II (Nav 1.5 activator) with an IC₅₀ value of 141 nM. Interestingly, Relutrigine inhibits the SCN8A mutation N1768D with an IC₅₀ value of 75 nM. Particularly, Relutrigine exhibits potent use-dependent blocks and reduces neuronal intrinsic excitability. Relutrigine has effective anticonvulsant activity.

Next in importance, Relutrigine has a stronger inhibitory effect on hNaV1.6 sustained sodium channel (I_Na) when compared with targeted antiepileptic drugs Carbamazepine and Lamotrigine. Relutrigine shows a preference for persistent I_Na. Relutrigine (0.3 µM) significantly reduces the intrinsic excitability of wild-type CA1 pyramidal neurons.

Once again, Relutrigine exhibits dose-dependent protection in mice against maximal electroshock seizure (MES) induced tonic hindlimb seizures. Obviously, Relutrigine results in dose-dependent reductions in distance moved within the male CD-1 mice model.

All in all, Relutrigine (PRAX-562) is an orally active inhibitor of the persistent sodium channel.

References:

[1]  Kahlig KM, et al. Epilepsia. 2022 Mar;63(3):697-708.