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Effects of besipirdine at the voltage‐dependent sodium channel

1 Besipirdine (HP 749) is a compound undergoing clinical trials for efficacy in treating Alzheimer's disease. Among other pharmacological effects, besipirdine inhibits voltage‐dependent sodium and potassium channels. This paper presents a pharmacological study of the interaction of besipirdine with voltage‐dependent sodium channels. 2 Besipirdine inhibited [3H]‐batrachotoxin binding (IC50 = 5.5±0.2 μm) in a rat brain vesicular preparation and concentration‐dependently inhibited veratridine (25 μm)‐stimulated increases in intracellular free sodium ([Na+]i) and calcium ([Ca2+]i) in primary cultured cortical neurones of rat. 3 Besipirdine (30–100 μm) concentration‐dependently inhibited (up to 100%) veratridine‐stimulated release of [3H]‐noradrenaline (NA) from rat cortical slices. 4 When examined in greater detail, besipirdine was found to inhibit [3H]‐batrachotoxin binding in vesicular membranes competitively. However, when examined in rat brain synaptosomes, we found that the antagonism by besipirdine was not competitive; that is, the maximal stimulation of [Ca2+]i induced by veratridine decreased with increasing concentrations of besipirdine. 5 These results show that besipirdine is an inhibitor of voltage‐sensitive sodium channels and appears to bind to a site close to the batrachotoxin/veratridine binding site.