GIRK Activator, ML297

Cell permeable: yes

Primary Target
GIRK1/K_ir3.1-containing tetrameric GIRK channels

Reversible: yes

Toxicity: Standard Handling (A)

A blood-brain barrier-permeable, non-toxic phenyl-pyrazolylurea compound that acts as a direct, potent, fast, and reversible activator of GIRK1 (G-protein activated inward-rectifying K⁺ channel containing subunit 1) containing channels (EC₅₀ = 162, 914, and 887 nM in Thallium influx assay for GIRK1/2, GIRK1/3, and GIRK1/4 expressed in HEK-293 cell lines). Its action does not require the presence of an activated G_i GPCR. Shown to be inactive towards GIRK2, GIRK2/3, K_ir2.1, K_V7.4 and GABA_A, and weakly active against a panel of 61 other receptors, ion channels, enzymes, transporters, and proteins even at higher concentration (~10 µM). Exhibits desirable pharmacokinetic properties with good solubility (17.5 µM), predicted hepatic clearance (88 ml/min/kg), and T_max of 640 nM and 130 nM in plasma and brain, respectively. Shown to reduce locomotor function and seizure frequency in electroshock- and chemically-induced murine epilepsy models (60 mg/kg, i.p).

A cell-permeable phenyl-pyrazolylurea that directly activates GIRK1/K_ir3.1-containing tetrameric GIRK channels (EC₅₀ = 162, 887 and 914 nM, respectively, in Thallium flux assays using GIRK1-2, GIRK1-4, or GIRK1-3 HEK-293 transfectants; EC₅₀ = 584 and 1,400 nM, respectively, in whole-cell voltage clamp measurements using GIRK1-2 or GIRK1-4 HEK-293 transfectants) in a GPCR-independent manner, while being ineffective toward K_ir2.1, K_V7.4, or GIRK channels composed of GIRK2-3 (K_ir3.2-K_ir3.3) or GIRK2 alone. Selectivity studies against 67 receptors reveal only weak antagonistic activity against hERG (IC₅₀ = 10 µM; Inh_max/IC_max = 59.6%/100 µM), rat GABA_A (muscimol), human Sigma δ1, and human 5-HT_2B receptors (49%, 49%, and 46% inhibition, respectively, at 10 µM). Despite its suboptimal metabolic stability and brain permeability in mice (C_max/T_maxmax = 130 nM/30 min; 60 mg/kg i.p.), ML297 nevertheless is demonstrated to be at least 4.9-times more effective than Valproate (Cat. No. 676380) in prolonging the latency to seizure following lethal electric shock and in preventing GABA_A antagonist PTZ-induced convulsion and death in two murine epilepsy models (60 mg/kg i.p.) in vivo.

Wen, W., et al. 2013. Bioorg. Med. Chem. Lett.23, 4562.
Kaufmann, K., et al. 2013. ACS Chem. Neurosci.4, 1278.

Packaged under inert gas

Use only fresh DMSO for reconstitution.

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany