PF-04856264

Voltage-gated sodium (Na_V) channels contribute to physiological and pathophysiological electrical signaling in nerve and muscle cells. The Na_V1.7 is highly expressed on the exons somatic afferent neurons and is thought to play an important role in the signaling of inflammatory pain.

PF-04856264, is a synthetic blocker of the human Na_V1.7 channel. It has an effective concentration of 10 nM - 1 μM and an IC₅₀ of 28 nM for Na_V1.7 channel in its inactive state. Na_V1.7 currents elicited by 20 ms depolarizing voltage steps from −120 mV are insensitive to inhibition by 1 µM PF-04856264, whereas the same concentration produced 91% ± 4% inhibition when a test pulse was preceded by an 8-s conditioning voltage step to inactivate approximately half of the channels. In contrast, Na_V1.3 and Na_V1.5 channels exhibit little or no sensitivity to inhibition by PF-04856264. Interestingly, different species orthologs exhibit different sensitivities to inhibition by PF. PF interacts with domain 4 voltage sensor M1,2,3 residues of the channel. When these extracellular residues are substituted with residues from the Na_V1.3 channel the blocking effect of PF is abolished. Given the involvement of Na_V in a variety of pathological conditions further research of subtype selective Na_V channel inhibitors may prove useful for developing future therapeutic agents.