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 microM) in a rat brain vesicular preparation and concentration-dependently inhibited veratridine (25 microM)-stimulated increases in intracellular free sodium ([Na+]i) and calcium ([Ca2+]i) in primary cultured cortical neurones of rat. 3. Besipirdine (30-100 microM) 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.