GIRK Activator, ML297

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.

Cell permeable: yes

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

Reversible: yes

Packaged under inert gas

Use only fresh DMSO for reconstitution.

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

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

Toxicity: Standard Handling (A)