Abstract
It has been recently published that a small molecule, A-803467, selectively inhibits hNav1.8 sodium channel subtype and is also efficacious in a variety of pre-clinical pain models (ref. 1). While A-803467 blocks hNav1.8 with an IC50 value of 8 nM (at half-maximal inactivation), it also inhibits other sodium channel subtypes with a selectivity ratio of 30-1000-fold. In particular, it inhibits hNav1.3 and hNav1.7 channels, which have connection to pain sensation in animal models (ref. 2), with IC50 values around 1 μM. We suggest that inhibition of these channels may also contribute to analgesic efficacy of A-803467. We therefore were interested in studying biophysical parameters of interaction of A-803467 with hNav1.7 and hNav1.3 channels. We present the data on the affinity of binding of the drug to the resting and inactivated states of the channels, as well as the on-rate of binding to inactivated channels, retardation of repriming and use-dependent block of trains of depolarizing pulses. The biophysical profile of A-803467 suggests interaction with a site distinct from the “classical” local anaesthetic receptor site in Nav channels. This profile is compared with the parameters measured for other clinically relevant analgesics.(1) Jarvis MF, et al. Proc Natl Acad Sci USA 2007; 104:8520-85.(2) Dib-Hajj SD, et al. Trends in Neurosciences 2007; 30 (11):555-63.
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