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Titolo:
1-ARYL-3,5-DIHYDRO-4H-2,3-BENZODIAZEPIN-4-ONES - NOVEL AMPA RECEPTOR ANTAGONISTS
Autore:
CHIMIRRI A; DESARRO G; DESARRO A; GITTO R; GRASSO S; QUARTARONE S; ZAPPALA M; GIUSTI P; LIBRI V; CONSTANTI A; CHAPMAN AG;
Indirizzi:
UNIV MESSINA,DIPARTIMENTO FARMACOCHIM,VIALE ANNUNZIATA I-98168 MESSINA ITALY UNIV REGGIO CALABRIA,DIPARTIMENTO MED SPERIMENTALE & CLIN CALABRIA ITALY UNIV MESSINA,FAC MED,IST FARMACOL I-98100 MESSINA ITALY UNIV PADUA,DIPARTIMENTO FARMACOL I-35100 PADUA ITALY UNIV ROMA TOR VERGATA,DIPARTIMENTO BIOL I-00173 ROME ITALY UNIV LONDON,SCH PHARM,DEPT PHARMACOL LONDON WC1N 1AX ENGLAND UNIV LONDON,INST PSYCHIAT,DEPT NEUROL LONDON SE5 8AF ENGLAND
Titolo Testata:
Journal of medicinal chemistry
fascicolo: 8, volume: 40, anno: 1997,
pagine: 1258 - 1269
SICI:
0022-2623(1997)40:8<1258:1-NARA>2.0.ZU;2-#
Fonte:
ISI
Lingua:
ENG
Soggetto:
NMDA GLUTAMATE RECEPTOR; D-ASPARTATE RECEPTOR; EPILEPSY-PRONE RATS; ANTICONVULSANT ACTIVITY; DBA/2 MICE; AUTORADIOGRAPHIC CHARACTERIZATION; MOLECULAR REQUIREMENT; QUISQUALATE RECEPTORS; REFLEX EPILEPSY; GYKI 52466;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
61
Recensione:
Indirizzi per estratti:
Citazione:
A. Chimirri et al., "1-ARYL-3,5-DIHYDRO-4H-2,3-BENZODIAZEPIN-4-ONES - NOVEL AMPA RECEPTOR ANTAGONISTS", Journal of medicinal chemistry, 40(8), 1997, pp. 1258-1269

Abstract

Our previous publication (Eur. J. Pharmacol. 1995, 294, 411-422) reported preliminary chemical and biological studies of some 2,3-benzodiazepines, analogues of -aminophenyl)4-methyl-7,8-(methylenedioxy)-5H-2,3- benzodiazepines (1, GYKI 52466), which have been shown to possess significant anticonvulsant activity. This paper describes the synthesis of new 1-aryl-3,5-dihydro-4H-2,3-benzodiazepin-4-ones and the evaluation of their anticonvulsant effects. The observed findings extend the structure-activity relationships previously suggested for this class ofanticonvulsants. The seizures were evoked both by means of auditory stimulation in DBA/2 mice and by pentylenetetrazole or maximal electroshock in Swiss mice. Aminophenyl)- (38) and (3'-aminophenyl)-3,5-dihydro-7,8-dimethoxy-4H-2,3- benzodiazepin-4-one (39), the most active compounds of the series, proved to be more potent than 1 in all tests employed. In particular, the ED(50) values against tonus evoked by auditory stimulation were 12.6 mu mol/kg for derivative 38, 18.3 mu mol/kg for 39, and 25.3 mu mol/kg for 1. Higher doses were necessary to block tonic extension induced both by maximal electroshock and by pentylenetetrazole. In addition these compounds exhibited anticonvulsant properties that were longer lasting than those of compound 1 and were less toxic. The novel 2,3-benzodiazepines were also investigated for a possible correlation between their anticonvulsant activities against convulsions induced by amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid(AMPA) and their affinities for benzodiazepine receptors (BZR). The 2,3-benzodiazepines did not affect the binding of [H-3]flumazenil to BZR, and conversely, their anticonvulsant effects were not reversed by flumazenil. On the other hand the 2,3-benzodiazepines antagonized seizures induced by AMPA and aniracetam in agreement with an involvement ofthe AMPA receptor. In addition, both the derivative 38 and the compound 1 markedly reduced the AMPA receptor-mediated membrane currents in guinea-pig olfactory cortical neurons in vitro in a noncompetitive manner. The derivatives 25 and 38-40 failed to displace specific ligands from N-methyl-D-aspartate (NMDA), AMPA/kainate, or metabotropic glutamate receptors.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 02/04/20 alle ore 12:28:15