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Titolo:
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
Autore:
Weiser, T; Brenner, M; Palluk, R; Bechtel, WD; Ceci, A; Brambilla, A; Ensinger, HA; Sagrada, A; Wienrich, M;
Indirizzi:
Boehringer Ingelheim Pharma KG, Dept CNS Res, D-55218 Ingelheim, Germany Boehringer Ingelheim Pharma KG Ingelheim Germany D-55218 elheim, Germany Boehringer Ingelheim Pharma KG, Dept Med Chem, Ingelheim, Germany Boehringer Ingelheim Pharma KG Ingelheim Germany em, Ingelheim, Germany Boehringer Ingelheim GmbH, Ingelheim, Germany Boehringer Ingelheim GmbH Ingelheim Germany im GmbH, Ingelheim, Germany Boehringer Ingelheim Italy, Milan, Italy Boehringer Ingelheim Italy Milan Italy er Ingelheim Italy, Milan, Italy
Titolo Testata:
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
fascicolo: 3, volume: 289, anno: 1999,
pagine: 1343 - 1349
SICI:
0022-3565(199906)289:3<1343:B5CANC>2.0.ZU;2-W
Fonte:
ISI
Lingua:
ENG
Soggetto:
RAT HIPPOCAMPAL-NEURONS; FOCAL CEREBRAL-ISCHEMIA; IIA NA+ CHANNELS; GYKI 52466; GLUTAMATE-RECEPTOR; MOUSE MODEL; BRAIN; LAMOTRIGINE; INHIBITION; AMPA;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
31
Recensione:
Indirizzi per estratti:
Indirizzo: Weiser, T Boehringer Ingelheim Pharma KG, Dept CNS Res, D-55218 Ingelheim,Germany Boehringer Ingelheim Pharma KG Ingelheim Germany D-55218 rmany
Citazione:
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

Abstract

Antagonists of glutamate receptors of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype, as well as of voltage-gated sodiumchannels, 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 mu M. The inhibition was noncompetitive. In a cortical wedge preparation, BIIR 561 CL reduced AMPA-induced depolarizations with an IC50 value of 10.8 mu M. 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 mu M. The compound reduced sodium currents in voltage-clamped cortical neurons with an IC50 value of 5.2 mu M and inhibited the veratridine-induced release 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 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.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 28/03/20 alle ore 23:32:46