Voltage-gated sodium channels are known to play a pivotal role in perception and transmission of
pain sensations. Gain-of-function mutations in the genes encoding the peripheral neuronal
sodium channels, hNav1.7-1.9, cause human painful diseases. Thus while treatment of
chronic pain remains an unmet clinical need,
sodium channel blockers are considered as promising druggable targets. In a previous study, we evaluated the
analgesic activity of
sumatriptan, an agonist of
serotonin 5HT1B/D receptors, and some new chiral bioisosteres, using the hot plate test in the mouse. Interestingly, we observed that the
analgesic effectiveness was not necessarily correlated to
serotonin agonism. In this study, we evaluated whether
sumatriptan and its congeners may inhibit heterologously expressed hNav1.7
sodium channels using the patch-clamp method. We show that
sumatriptan blocks hNav1.7 channels only at very high, supratherapeutic concentrations. In contrast, its three analogs, namely 20b, (R)-31b, and (S)-22b, exert a dose and use-dependent
sodium channel block. At 0.1 and 10 Hz stimulation frequencies, the most potent compound, (S)-22b, was 4.4 and 1.7 fold more potent than the well-known
sodium channel blocker mexiletine. The compound induces a negative shift of voltage dependence of fast inactivation, suggesting higher affinity to the inactivated channel. Accordingly, we show that (S)-22b likely binds the conserved
local anesthetic receptor within
voltage-gated sodium channels. Combining these results with the previous ones, we hypothesize that use-dependent
sodium channel blockade contributes to the
analgesic activity of (R)-31b and (S)-22b. These later compounds represent promising lead compounds for the development of efficient
analgesics, the mechanism of action of which may include a dual action on
sodium channels and 5HT1D receptors.