BIIR 561 CL: A novel combined antagonist of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and voltage-dependent sodium channels with anticonvulsive and neuroprotective properties
T. Weiser et al., BIIR 561 CL: A novel combined antagonist of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and voltage-dependent sodium channels with anticonvulsive and neuroprotective properties, J PHARM EXP, 289(3), 1999, pp. 1343-1349
Citations number
31
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Antagonists of glutamate receptors of the alpha-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid (AMPA) subtype, as well as of voltage-gated sodium
channels, exhibit anticonvulsive and neuroprotective properties in vivo. On
e can postulate that a compound that combines both principles might be usef
ul for the treatment of disorders of the central nervous system, like focal
or global ischemia. Here, we present data on the effects of dimethyl-{2-[2
-(3-phenyl-[1,2,4]oxadiazol-5-yl)-phenoxy]ethyl}amine hydrochloride (BIIR 5
61 CL) on neuronal AMPA receptors and voltage-dependent sodium channels. BI
IR 561 CL inhibited AMPA receptor-mediated membrane currents in cultured co
rtical neurons with an IC50 value of 8.5 mu M. The inhibition was noncompet
itive. In a cortical wedge preparation, BIIR 561 CL reduced AMPA-induced de
polarizations with an IC50 value of 10.8 mu M. In addition to the effects o
n the glutamatergic system, BIIR 561 CL inhibited binding of radiolabeled b
atrachotoxin to rat brain synaptosomal membranes with a K-i value of 1.2 mu
M. The compound reduced sodium currents in voltage-clamped cortical neuron
s with an IC50 value of 5.2 mu M and inhibited the veratridine-induced rele
ase of glutamate from rat brain slices with an IC50 value of 2.3 mu M. Thus
, BIIR 561 CL inhibited AMPA receptors and voltage-gated sodium channels in
a variety of preparations. BIIR 561 CL suppressed tonic seizures in a maxi
mum electroshock model in mice with an ED50 value of 2.8 mg/kg after s.c. a
dministration. In a model of focal ischemia in mice, i.p. administration of
6 or 60 mg/kg BIIR 561 CL reduced the area of the infarcted cortical surfa
ce. These data show that BIIR 561 CL is a combined antagonist of AMPA recep
tors and voltage-gated sodium channels with promising anticonvulsive and ne
uroprotective properties.