ML204

Description: ML204 is a novel, potent, and selective TRPC4 (Transient receptor potential canonical) channel inhibitor identified from high throughput fluorescent screen of 305, 000 compounds of the Molecular Libraries Small Molecule Repository for inhibitors that blocked intracellular Ca(2+) rise in response to stimulation of mouse TRPC4beta by u-opioid receptors. ML204 inhibited TRPC4beta-mediated intracellular Ca(2+) rise with an IC(50) value of 0.96 um and exhibited 19-fold selectivity against muscarinic receptor-coupled TRPC6 channel activation. In whole-cell patch clamp recordings, ML204 blocked TRPC4beta currents activated through either u-opioid receptor stimulation or intracellular dialysis of guanosine 5'-3-O-(thio)triphosphate (GTPgammaS), suggesting a direct interaction of ML204 with TRPC4 channels rather than any interference with the signal transduction pathways. Selectivity studies showed no appreciable block by 10-20 um ML204 of TRPV1, TRPV3, TRPA1, and TRPM8, as well as KCNQ2 and native voltage-gated sodium, potassium, and calcium channels in mouse dorsal root ganglion neurons. In isolated guinea pig ileal myocytes, ML204 blocked muscarinic cation currents activated by bath application of carbachol or intracellular infusion of GTPgammaS, demonstrating its effectiveness on native TRPC4 currents. Therefore, ML204 represents an excellent novel tool for investigation of TRPC4 channel function and may facilitate the development of therapeutics targeted to TRPC4.

References: J Biol Chem. 2011 Sep 23; 286(38):33436-46.

Related CAS#:2070015-10-8 (HCl)