ML252

ML252 is a potent, brain penetrant potassium channel Kv7.2 (KCNQ2) inhibitor with an IC₅₀ of 69 nM. ML252 is only slightly selective over KCNQ3 and KCNQ4 but is over 40-fold selective for KCNQ2 vs KCNQ1, unlike other KCNQ inbhibitors currently used. ML252 was also selective vs. >68 tested GPCRs, ion channels, and transporters. Potassium channel Kv7.2 has become a new target for Alzheimer′s Disease drug research because inhibiting it enhances acetylcholine release. SAR studies showed a small structural change from ethyl group to hydrogen resulted in a functional shift from antagonist to agonist activity (37, EC₅₀ of 170 nM), suggesting an interaction at a critical site for controlling KCNQ2 channel gating.