Voltage-gated calcium channels (VGCC) are a group of voltage-gated ion channels in the membrane of excitable cells. Specifically, they have permeability to calcium ion Ca2+. This channel is a key sensor for the change of membrane potential into intracellular Ca2+ transient. And this can trigger many physiological events. Besides, VGCC family has 10 members, which play different roles in cell signal transduction. Cav channels play a dual role in cells. Moreover, they can depolarize the membrane potential to achieve electrical excitability. They activate the transient cytoplasmic Ca2+ signal.
Furthermore, there are three main subdivisions of calcium channels, the Cav1, Cav2, and Cav3 channels. Meanwhile, α2δ and β Subunits also play an important role in channel folding and its subsequent transport to the cell surface and into specific areas of polarized cells, such as neurons. Nonetheless, VGCC control key functions of excitable cells, such as synaptic transmission in neurons and contraction of heart and skeletal muscle. Here, we will introduce a selective and orally available ligand for the α2δ subunit of voltage-gated calcium channels, Mirogabalin besylate.
Mirogabalin besylate is a Selective and Orally Active Ligand for the α2δ Subunit of Voltage-Gated Calcium Channels.
At first, Mirogabalin besylate has Kds of 13.5 nM, 22.7 nM, 27 nM, and 47.6 nM for human α2δ-1, human α2δ-2, rat α2δ-1, and rat α2δ-2, respectively. Importantly, Mirogabalin shows binding affinity for the gabapentin binding site in rat cortical brain homogenates with the IC50 value of 16.0 nM. Particularly, Mirogabalin has no effect on any other receptors, channels, transporters, or enzymes at 50 μM.
Secondly, Mirogabalin besylate with 3 and 10 mg/kg markedly increases AUC0-8 hours values in a dose-dependent manner in partial sciatic nerve ligation model rats. Obviously, Mirogabalin causes a significant and dose-dependent increase in AUC0-12 hours values and enhances analgesic effects. In particular, it has estimated ED50 of 4.4, 3.1, and <2.5 mg/kg on day 1, day 3, and day 5, respectively. Moreover, Mirogabalin besylate shows no obvious effect on rota-rod performance and locomotor activity.
Thirdly, Mirogabalin besylate exhibits significant inhibition on rota-rod performance at 10, 30, and 100 mg/kg. Additionally, Mirogabalin besylate decreases locomotor activity at 30 and 100 mg/kg in rats
Finally, Mirogabalin besylate is a selective and orally available ligand for the α2δ subunit of voltage-gated calcium channels.
Domon Y, et al. J Pharmacol Exp Ther. 2018 Jun;365(3):573-582.