Luzindole and ramelteon share a melatonin receptor-independent blocking effect on voltage-gated potassium KV4.2 channels.

Melatonin is a pineal hormone that regulates circadian rhythms primarily through melatonin receptors. We recently demonstrated that melatonin inhibits the voltage-gated potassium KV4.2 channel (IC50 = 479 μM) through a melatonin receptor-independent mechanism. However, it remains unclear whether this inhibitory effect is specific to melatonin or shared by structurally related compounds. In the present study, we examined the effects of melatonin-related compounds on KV4.2 channels using human embryonic kidney 293 cells stably expressing KV4.2 channels. Whole-cell patch-clamp recordings showed that luzindole, a melatonin receptor antagonist, inhibited KV4.2 currents (IC50 = 33 μM). Notably, ramelteon, a melatonin receptor agonist, also inhibited KV4.2 currents (IC50 = 177 μM). These results indicate that the inhibitory effects of luzindole and ramelteon are mediated by direct interactions with KV4.2 channels rather than through melatonin receptors. In addition, luzindole inhibited KV1.5 channels. In contrast, melatonin biosynthetic precursors failed to inhibit KV4.2 currents, suggesting that the indole or indole-like structural motif alone is insufficient for KV4.2 channel inhibition. Instead, specific structural features, including the methoxy group in melatonin and the furan ring in ramelteon, together with increased hydrophobicity, may be critical determinants of KV4.2 channel blockade. Collectively, these findings reveal previously unrecognized pharmacological properties of melatonin-related compounds.