Securinine alkaloids: a new class of GABA receptor antagonist.

Experiments were undertaken to determine the site of action of securinine and related convulsant indolizidines. All of these compounds induced tonic seizures in mice, with CD50 values ranging from 11 to 87 mg/kg. The CD50 for bicuculline was found to be 8 mg/kg. Equilibrium binding assays revealed that securinine and dihydrosecurinine inhibit [3H]GABA binding to rat brain membranes with an IC50 of approximately 50 microM, which is some 7 times less potent than bicuculline. Allosecurinine and virosecurinine have IC50 values greater than 1 mM. Both dihydrosecurinine and securinine inhibited GABA-stimulated benzodiazepine binding in rat brain membranes, though they were somewhat weaker than bicuculline in this respect. Other binding assays revealed that securinine and its analogs were inactive as inhibitors of bicuculline-insensitive GABA binding, benzodiazepine, cholinergic muscarinic, and beta-adrenergic receptor binding. In addition, while thiocyanate ion increased the apparent binding potency of bicuculline 10-fold, it had little effect on that of securinine. Extracellular electrophysiological studies on neurons in the cat spinal cord indicated that securinine and dihydrosecurinine blocked the inhibitory action of GABA while having no effect on that of glycine. Allo- and virosecurinine were much less active as GABA receptor antagonists in this test. These results suggest that, like bicuculline, securinine and dihydrosecurinine are selective antagonists of GABA recognition sites on mammalian central neurons.