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Effects of besipirdine at the voltage‐dependent sodium channel
Author(s) -
Tang L.,
Smith C.P.,
Huger F.P.,
Kongsamut S.
Publication year - 1995
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1995.tb15097.x
Subject(s) - batrachotoxin , veratridine , sodium channel , sodium , chemistry , synaptosome , stimulation , biophysics , pharmacology , biochemistry , endocrinology , biology , membrane , organic chemistry
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 [ 3 H]‐batrachotoxin binding (IC 50 = 5.5±0.2 μ m ) in a rat brain vesicular preparation and concentration‐dependently inhibited veratridine (25 μ m )‐stimulated increases in intracellular free sodium ([Na + ] i ) and calcium ([Ca 2+ ] i ) in primary cultured cortical neurones of rat. 3 Besipirdine (30–100 μ m ) concentration‐dependently inhibited (up to 100%) veratridine‐stimulated release of [ 3 H]‐noradrenaline (NA) from rat cortical slices. 4 When examined in greater detail, besipirdine was found to inhibit [ 3 H]‐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 [Ca 2+ ] 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.