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

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.