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Titolo:
STRUCTURE-ACTIVITY-RELATIONSHIPS IN A SERIES OF 2(1H)-QUINOLONES BEARING DIFFERENT ACIDIC FUNCTION IN THE 3-POSITION - 6,7-DICHLORO-2(1H)-OXOQUINOLINE-3-PHOSPHONIC ACID, A NEW POTENT AND SELECTIVE AMPA KAINATEANTAGONIST WITH NEUROPROTECTIVE PROPERTIES/
Autore:
DESOS P; LEPAGNOL JM; MORAIN P; LESTAGE P; CORDI AA;
Indirizzi:
INST RECH SERVIER,11 RUE MOULINEAUX F-92150 SURESNES FRANCE INST RECH SERVIER F-92150 SURESNES FRANCE
Titolo Testata:
Journal of medicinal chemistry
fascicolo: 1, volume: 39, anno: 1996,
pagine: 197 - 206
SICI:
0022-2623(1996)39:1<197:SIASO2>2.0.ZU;2-H
Fonte:
ISI
Lingua:
ENG
Soggetto:
D-ASPARTATE RECEPTOR; METHYL-D-ASPARTATE; GLYCINE-SITE NMDA; SYNAPTIC POTENTIALS; DERIVATIVES; ISCHEMIA; AMPA; INHIBITION; CURRENTS; CLONING;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
38
Recensione:
Indirizzi per estratti:
Citazione:
P. Desos et al., "STRUCTURE-ACTIVITY-RELATIONSHIPS IN A SERIES OF 2(1H)-QUINOLONES BEARING DIFFERENT ACIDIC FUNCTION IN THE 3-POSITION - 6,7-DICHLORO-2(1H)-OXOQUINOLINE-3-PHOSPHONIC ACID, A NEW POTENT AND SELECTIVE AMPA KAINATEANTAGONIST WITH NEUROPROTECTIVE PROPERTIES/", Journal of medicinal chemistry, 39(1), 1996, pp. 197-206

Abstract

Recently, we reported the synthesis of 3-(sulfonylamino)-2(1H)-quinolones, a new series of lpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate and N-methyl-D-aspartic acid (NMDA)/glycine antagonists. By exploring the structure-activity relationships (SAR) in this series, we were able to identify the 6,7-dinitro derivative 6 as apotent and balanced antagonist at both receptors. Unfortunately, compound 6 was devoid of in vivo activity in mice anticonvulsant testing. To overcome this critical limitation, new compounds bearing various acidic oieties at the 3-position of the quinolone skeleton were synthesized and evaluated. The SAR of these new analogues indicated that not all acidic groups are acceptable at the 3-position: A rank order of potency going from carboxylic approximate to phosphonic > tetrazole > mercaptoacetic > hydroxamic much greater than other heterocyclic acids was defined. In addition, the selectivity between the AMPA/kainate and NMDA/glycine sites is dependent on the nature of the substitution (nitro > chloro for AMPA selectivity), its position (5,7- > 6,7-pattern forglycine selectivity), and the distance between the quinolone moiety and the heteroatom bearing the acidic hydrogen (the longer the distancethe more ,MPA selective the compound). Among these new AMPA antagonists, we have identified 6,7-dichloro-2(-oxoquinoline-3-phosphonic acid (24c) as a water soluble and selective compound endowed with an appealing pharmacologicalprofile. Compared with the reference AMPA antagonist NBQX, the phosphonic acid 24c is much less potent in vitro but almost equipotent in vivo in the audiogenic seizures model after intraperitoneal administration. Moreover, unlike NBQX, compound 24c is also active after oral administration. In the gerbil global ischemia model, compound 24c shows a neuroprotective effect at 10 mg/kg/ip, equivalent tothe reference NBQX.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 01/10/20 alle ore 03:03:24