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Falcarindiol (1), a C-17 polyacetylenic diol, shows a pleiotropic profile of bioactivity, but the mechanism(s) underlying its actions are largely unknown. Large amounts of 1co-occur in water hemlock (Oenanthe crocata) along with the convulsant polyacetylenic toxin oenanthotoxin (2), a potent GABAAreceptor (GABAAR) inhibitor. Since these compounds are structurally and biogenetically related, it was considered of interest to evaluate whether 1could affect GABAergic activity, and for this purpose a model of hippocampal cultured neurons was used. Compound 1significantly increased the amplitude of miniature inhibitory postsynaptic currents, accelerated their onset, and prolonged the decay kinetics. This compound enhanced also the amplitude of currents elicited by 3 μM GABA and accelerated their fading, reducing, however, currents evoked by a saturating (10 mM) GABA concentration. Moreover, kinetic analysis of responses to 10 mM GABA revealed that 1upregulated the rate and extent of desensitization and slowed the current onset and deactivation. Taken together, these data show that 1exerts a potent modulatory action on GABAARs, possibly by modulating agonist binding and desensitization, overall potentially decreasing the toxicity of co-occurring GABA-inhibiting convulsant toxins.

An investigation of Oenanthe fistulosafrom Sardinia afforded oenanthotoxin (1a) and dihydrooenanthotoxin (1b) from the roots and the diacetylenic epoxydiol 2from the seeds. The absolute configuration of 1aand 1bwas established as Rby the modified Mosher’s method, and the structure of 2by chemical correlation with (+)-(3R,8S)-falcarindiol. Oenanthotoxin (1a) and dihydrooenanthotoxin (1b) were found to potently block GABAergic responses, providing a molecular rationale for the symptoms of poisoning from water-dropwort (Oenanthe crocata) and related plants. These observations bear relevance for a series of historical and ethnopharmacological observations on the identification of the Sardonic herb and the molecular details of the facial muscular contraction caused by its ingestion (risus sardonicus).