Vol. 289, Issue 3, 1343-1349, June 1999

BIIR 561 CL: A Novel Combined Antagonist of -Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptors and Voltage-Dependent Sodium Channels with Anticonvulsive and Neuroprotective Properties

T. Weiser, M. Brenner, R. Palluk, W. D. Bechtel, A. Ceci, A. Brambilla, H. A. Ensinger, A. Sagrada and M. Wienrich

Boehringer Ingelheim Pharma KG, Department of CNS Research, Ingelheim, Germany (T.W., W.D.B., H.A.E.); Boehringer Ingelheim Pharma KG, Department of Medicinal Chemistry, Ingelheim, Germany (M.B.); Boehringer Ingelheim GmbH, Ingelheim, Germany (R.P., M.W.); and Boehringer Ingelheim Italy, Milan, Italy (A.C., A.B., A.S.)

Antagonists of glutamate receptors of the -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. One can postulate that a compound that combines both principles might be useful 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 561 CL) on neuronal AMPA receptors and voltage-dependent sodium channels. BIIR 561 CL inhibited AMPA receptor-mediated membrane currents in cultured cortical neurons with an IC₅₀ value of 8.5 µM. The inhibition was noncompetitive. In a cortical wedge preparation, BIIR 561 CL reduced AMPA-induced depolarizations with an IC₅₀ value of 10.8 µM. In addition to the effects on the glutamatergic system, BIIR 561 CL inhibited binding of radiolabeled batrachotoxin to rat brain synaptosomal membranes with a K_i value of 1.2 µM. The compound reduced sodium currents in voltage-clamped cortical neurons with an IC₅₀ value of 5.2 µM and inhibited the veratridine-induced release of glutamate from rat brain slices with an IC₅₀ value of 2.3 µM. 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 maximum electroshock model in mice with an ED₅₀ value of 2.8 mg/kg after s.c. administration. 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 surface. These data show that BIIR 561 CL is a combined antagonist of AMPA receptors and voltage-gated sodium channels with promising anticonvulsive and neuroprotective properties.