Frequency-dependent inhibition of neurotransmitter release by besipirdine and HP 184

We have described the interaction of besipirdine (HP 749, N-(n-propyl)-N-(4-pyridinyl)-1H-indol-1-amine hydrochloride) with voltage-dependent Na+ channels (Tang et al., 1995, Br. J. Pharmacol. 116,2468). Here we describe studies with besipirdine and a related compound, HP 184 (N-(n-propyl)-3-fluoro-4-pyridinyl)-1H-3-methylindol-1-amine hydrochloride), showing that this interaction is voltage-dependent and leads to frequency-dependent inhibition of electrically stimulated neurotransmitter release. Thus, the inhibition of veratridine-induced increases in intracellular Ca2+ was enhanced by depolarization with KCl (IC50 shifted from 23.8 +/- 1.4 microM in 5 mM KCl to 7.3 +/- 1.2 microM in 15 mM KCl for besipirdine and from 58.2 +/- 1.3 microM for HP 184). Moreover, the enhancement of electrically stimulated [3H]norepinephrine release by besipirdine was diminished at higher frequencies of stimulation. As has been previously suggested for such compounds, we predict that besipirdine would act as a filter in the brain allowing signalling at low frequencies but blocking transmission at high frequencies.