Our previous studies implicated the
voltage-gated sodium channel subtype NaV 1.7 in the transmission of action potentials by the vagal afferent nerves regulating
cough and thus identified this channel as a rational therapeutic target for
antitussive therapy. But it is presently unclear whether a systemically administered small molecule inhibitor of NaV 1.7 conductance can achieve therapeutic benefit in the absence of side effects on cardiovascular function, gastrointestinal motility or respiration. To this end, we have evaluated the
antitussive effects of the NaV 1.7 selective blocker Compound 801 administered systemically in awake guinea pigs or administered topically in anesthetized guinea pigs. We also evaluated the
antitussive effects of
ambroxol, a low affinity NaV blocker modestly selective for
tetrodotoxin resistant NaV subtypes. Both Compound 801 and
ambroxol dose-dependently inhibited action potential conduction in guinea pig vagus nerves (assessed by compound potential), with
ambroxol nearly 100-fold less potent than the NaV 1.7 selective Compound 801 in this and other NaV 1.7-dependent guinea pig and human tissue-based assays. Both drugs also inhibited
citric acid evoked coughing in awake or anesthetized guinea pigs, with potencies supportive of an NaV 1.7-dependent mechanism. Notably, however, the
antitussive effects of systemically administered Compound 801 were accompanied by
hypotension and
respiratory depression. Given the
antitussive effects of topically administered Compound 801, we speculate that the likely insurmountable side effects on blood pressure and respiratory drive associated with systemic dosing make topical formulations a viable and perhaps unavoidable therapeutic strategy for targeting NaV 1.7 in
cough.