Here,
we report the discovery of a novel anticonvulsant drug with
a molecular organization based on the unique scaffold of rufinamide,
an anti-epileptic compound used in a clinical setting to treat severe
epilepsy disorders such as Lennox-Gastaut syndrome. Although accumulating
evidence supports a working mechanism through voltage-gated sodium
(Nav) channels, we found that a clinically relevant rufinamide
concentration inhibits human (h)Nav1.1 activation, a distinct
working mechanism among anticonvulsants and a feature worth exploring
for treating a growing number of debilitating disorders involving
hNav1.1. Subsequent structure–activity relationship
experiments with related N-benzyl triazole compounds
on four brain hNav channel isoforms revealed a novel drug
variant that (1) shifts hNav1.1 opening to more depolarized
voltages without further alterations in the gating properties of hNav1.1, hNav1.2, hNav1.3, and hNav1.6; (2) increases the threshold to action potential initiation in
hippocampal neurons; and (3) greatly reduces the frequency of seizures
in three animal models. Altogether, our results provide novel molecular
insights into the rational development of Nav channel-targeting
molecules based on the unique rufinamide scaffold, an outcome that
may be exploited to design drugs for treating disorders involving
particular Nav channel isoforms while limiting adverse
effects.
GABA A receptors shape synaptic transmission by modulating Cl − conductance across the cell membrane. Remarkably, animal toxins that specifically target GABA A receptors have not been identified. Here, we report the discovery of micrurotoxin1 (MmTX1) and MmTX2, two toxins present in Costa Rican coral snake venom that tightly bind to GABA A receptors at subnanomolar concentrations. Studies with recombinant and synthetic toxin variants on hippocampal neurons and cells expressing common receptor compositions suggest that MmTX1 and MmTX2 allosterically increase GABA A receptor susceptibility to agonist, thereby potentiating receptor opening as well as desensitization, possibly by interacting with the α + /β − interface. Moreover, hippocampal neuron excitability measurements reveal toxin-induced transitory network inhibition, followed by an increase in spontaneous activity. In concert, toxin injections into mouse brain result in reduced basal activity between intense seizures. Altogether, we characterized two animal toxins that enhance GABA A receptor sensitivity to agonist, thereby establishing a previously unidentified class of tools to study this receptor family.
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