VU0456810

Description

ML297 (1443246-62-5) is a selective GIRK 1/2 (Kir3.1/3.2) channel activator, IC50?= 160, 887 and 914 nM for GIRK1/2, GIRK1/4 and GIRK1/3 respectively. Has no effect on GIRK2, GIRK2/3, Kir2.1 and Kv7.4 channels.1,2??Displays antiseizure activity2?and decreases anxiety-related behavior without sedative or addictive effects3. Reduces glucose- and IBMX-stimulated GLP-1 secretion with no effect on GIP in murine L and K cells.4?Brain penetrant.

The Uses of VU0456810

ML 297 is an anxiolytic drug which acts as a selective Kir3.1/3.2 (GIRK1/2) channel activator. It may be used in the treatment of epileptic seizures.

in vitro

in thallium flux assays, ml297 showed concentration-dependent efficacy when tested on cells expressing girk1/2. ml297 could also activate girk channels comprised of girk1/3 and girk1/4 subunit combinations. however, ml297 diaplayed a complete inability to modulate the activity of hek-293 cells expressing girk2 alone. a similar complete lack of efficacy was seen when ml297 was tested on hek-293 cells expressing girk2/3. therefore, it appeared that ml297 is only capable of activating girk channels containing a girk1 subunit [1].

in vivo

previous study performed an ascending dose study in mice and it was found that the animals appeared normal and not under obvious distress at all doses tested. ml297’s effects on locomotor activity as well as effects on motor function and coordination were further evaluated. results showed that ml297 at 60 mg/kg could immediate decrease in locomotor activity compared to the control group [1].

storage

Store at -20°C

References

1) Wen?et al.?(2014),?Discovery of potent and selective GIRK1/2 modulators via “molecular switches’ within a series of 1-(3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl)ureas; Bioorg. Med. Chem. Lett.,?24?5102 2) Kaufmann?et al. (2013),?ML-297 (VU0456810), the first potent and selective activator of the GIRK potassium channel, displays antiepileptic properties in mice; ACS Chem. Neurosci.,?4?1278 3) Wydeven?et al.?(2014),?Mechanisms underlying the activation of G-protein-gated inwardly rectifying K+ (GIRK) channels by the novel anxiolytic drug, ML297; Proc. Natl. Acad. Sci. USA,?111?10755 4) Psichas?et al.?(2016),?Galanin inhibits GLP-1 and GIP secretion via the GAL1 receptor in enteroendocrine L and K cells; Br. J. Pharmacol.,?173?888