tcsc7802 ML402

ML402 is a selective TREK-1 activator.

IC50 & Target: TREK-1^[1]

In Vitro: Xenopus oocyte two-electrode voltage-clamp measurements show that ML335 and ML402 activate K_2P2.1 and K_2P10.1 but not K_2P4.1(14.3±2.7 μM, K_2P2.1-ML335; 13.7±7.0 μM, K_2P2.1-ML402; 5.2±0.5 μM, K_2P10.1-ML335; and 5.9±1.6 μM, K_2P10.1-ML402). The K_2P modulator pocket has a single difference among TREK subfamily members at the cation-π interaction position, K_2P2.1 Lys271, which is also a lysine in K_2P10.1 but a glutamine in K_2P4.1.

Swapping the Lys271 equivalent between K_2P2.1 and K_2P4.1 results in a clear phenotype reversal for ML335 and M402 activation. K_2P2.1 (K271Q) is insensitive to ML335 and ML402, whereas K_2P4.1 (Q258K) responds to both with a similar EC₅₀ to K_2P2.1 (14.3±2.7 μM, K_2P2.1-ML335; 16.2±3.0 μM, K_2P4.1(Q258K)-ML335; 13.7±7.0 μM, K_2P2.1-ML402; 13.6±1.5 μM, K_2P4.1 (Q258K)-ML402) but with a lower magnitude response than K_2P2.1^[1].