Voltage-dependent sodium channel blocker

Carter, R. B., Vanover, K. E., Wilent, W., Xu, Z., Woodward, R. M., Illyin, V. I. Anti-allodynic and anti-hyperalgesic effects of the novel voltage-dependent sodium channel blocker Co102862 in a rat model of peripheral neuropathy, Adv. Ion Channel Res., San Francisco 1999, Abstract book, P-... 

FIGURE 31.2 At 10 nM, palytoxin-induced a rapid increase in the intracellular sodium concentration in cultured cerebellar granule cells. This effect of palytoxin was sensitive to the voltage-dependent sodium channel blocker saxitoxin. Data are means sem of three independent experiments, each performed in duplicate. Drugs were added at the time points indicated by the arrows. 

The neurotoxins TTX and STX bind with similar affinity to all conformational states. Most other small molecule sodium channel blockers appear to interact preferentially with the open state, an inactivated state, or a combination of open and inactivated states. Since channel residence in these states is controlled by membrane voltage, state-dependent sodium channel blockers show both voltage- and use-dependence, i.e., their potency increases with more depolarized holding potentials and higher frequency stimulation [8-10]. 

A series of potent alkaloids were first isolated from den-drobatid frogs of western Colombia and northwestern Ecuador, but are now known to be more widespread in distribution. These alkaloids affect at least three classes of channels in nerve and muscle. The first two are receptor-regulated channels, in particular the nicotinic acetylcholine receptor channel. The histrionicotoxins are noncompetitive blockers of this receptor-channel complex (Daly et al, 1993). The second class of channels are the voltage-dependent sodium channels. Histrionicotoxins reduce conductances in a manner reminiscent of local anesthetics (Daly et al., 1993). Despite these effects, these alkaloids have relatively low toxicity (Daly et al., 1993). 

Sodium channel blockers including local anesthetic, anticonvulsant and antiarrhythmic drugs exhibit voltage- and frequency-dependent blockade which makes them useful drugs for blocking hyperexcitable neurons... 

Acts as a use-dependent blocker of voltage-sensitive sodium channels... 

There was some interest in the isobutylamides derived from various plant species including affinin (Figure 3.25) from Heliopsis longipes and pipercide (Figure 3.25) from Piper nigrum. These compounds are potent voltage-dependent blockers of the sodium channel but are too unstable to be used as products directly. 

Derived from lamotrigine (Glaxo Wellcome), The compound is a potent voltage- and frequency-dependent blocker of TTX-resitant and TTX-sensitive sodium channels. The compound induces anti-hyperalgesic and anti-allodynic effects in animal models of chronic neuropathic and inflammatory pain... 

---