The G-protein activated, inward-rectifying potassium (K+) channels, “GIRKs”, are a family of ion channels (Kir3.1-Kir3.4). Besides, GIRKs are comprised of various homo- and heterotetrameric combinations of four different subunits. In addition, These subunits are expressed in different combinations in a variety of regions throughout the central nervous system and in the periphery. Moreover, The body of GIRK research implicates GIRK in processes as diverse as controlling heart rhythm to modulation of response to analgesics. Pertussis toxin-sensitive G-protein-coupled receptors of the Gi subtype through interactions with the G-protein’s β/γ subunits can activate GIRK channels. Furthermore, GIRKs has widely expressed in the brain with the GIRK1/2 subunit combination being the most common and widespread. ML297 (VU 0456810) is a potent and selective GIRK1/2 activator for the treatment of epilepsy.
ML297 is a potent and selective GIRK1/2 activator, with an EC50 of 0.16 μM. Specifically, ML297 is the potential for the treatment of epilepsy. Nonetheless, ML297 is active in two in vivo models of epilepsy. While ML297 shows exquisite selectivity when considering GIRK1 vs non-GIRK1-containing GIRKs. It only shows a modest preference for the activation of the GIRK1/2 subunit combination versus GIRK1/3 or GIRK1/4, with a 6-fold range. Meanwhile, ML297 showed a highly significant ability to prevent convulsions. Finally, it prevented the fatality of the PTZ treatment with most of the animals treated with ML297 experiencing neither convulsions nor death. All in all, ML 297 is a potent and selective GIRK1/2 activator for the treatment of epilepsy.
Kaufmann K, et al. ACS Chem Neurosci. 2013 Sep 18;4(9):1278-86.