The study identifies ML252 as a potent, brain-penetrant KCNQ2 channel inhibitor and demonstrates that a minor structural modification can switch the molecule's function from antagonist to agonist.
No immediate clinical role for KCNQ2 modulators; leaves open whether structural switching enables bidirectional channel ligands in vivo.
A potent and selective inhibitor of KCNQ2, (S)-5 (ML252, IC(50) = 69 nM), was discovered after a high-throughput screen of the MLPCN library was performed. SAR studies revealed a small structural change (ethyl group to hydrogen) caused a functional shift from antagonist to agonist activity (37, EC(50) = 170 nM), suggesting an interaction at a critical site for controlling gating of KCNQ2 channels.
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Cheung et al. (2012) studied this question.
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