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Titolo:
Molecular modeling and QSAR analysis of the interaction of flavone derivatives with the benzodiazepine binding site of the GABA(A) receptor complex
Autore:
Marder, M; Estiu, G; Blanch, LB; Viola, H; Wasowski, C; Medina, JH; Paladini, AC;
Indirizzi:
Univ Buenos Aires, Fac Farm & Bioquim, Inst Quim & Fisicoquim Biol, RA-1113 Buenos Aires, DF, Argentina Univ Buenos Aires Buenos Aires DF Argentina RA-1113 Aires, DF, Argentina Natl Univ La Plata, Fac Ciencias Exactas, Dept Quim, CEQUINOR, RA-1900 La Plata, Argentina Natl Univ La Plata La Plata Argentina RA-1900 A-1900 La Plata, Argentina Natl Univ La Plata, Fac Ciencias Exactas, Dept Ciencias Biol, Div Farm, RA-1900 La Plata, Argentina Natl Univ La Plata La Plata Argentina RA-1900 A-1900 La Plata, Argentina Univ Buenos Aires, Fac Med, Inst Biol Celular & Neurociencias, RA-1121 Buenos Aires, DF, Argentina Univ Buenos Aires Buenos Aires DF Argentina RA-1121 Aires, DF, Argentina
Titolo Testata:
BIOORGANIC & MEDICINAL CHEMISTRY
fascicolo: 2, volume: 9, anno: 2001,
pagine: 323 - 335
SICI:
0968-0896(200102)9:2<323:MMAQAO>2.0.ZU;2-O
Fonte:
ISI
Lingua:
ENG
Soggetto:
HIGH-AFFINITY LIGAND; AMINOBUTYRIC ACID(A) RECEPTORS; ANTAGONISTIC PROPERTIES; INTRINSIC ACTIVITY; RAT-BRAIN; SUBTYPES; PHARMACOLOGY; 6-BROMO-3'-NITROFLAVONE; IMIDAZOBENZODIAZEPINES; 6,3'-DINITROFLAVONE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
54
Recensione:
Indirizzi per estratti:
Indirizzo: Paladini, AC Univ Buenos Aires, Fac Farm & Bioquim, Inst Quim & FisicoquimBiol, Junin 956, RA-1113 Buenos Aires, DF, Argentina Univ Buenos Aires Junin 956 Buenos Aires DF Argentina RA-1113
Citazione:
M. Marder et al., "Molecular modeling and QSAR analysis of the interaction of flavone derivatives with the benzodiazepine binding site of the GABA(A) receptor complex", BIO MED CH, 9(2), 2001, pp. 323-335

Abstract

A large number of structurally different classes of ligands, many of them sharing the main characteristics of the benzodiazepine (BDZ) nucleus, are active in the modulation of anxiety, sedation, convulsion, myorelaxation, hypnotic and amnesic states in mammals. These compounds have high affinity for the benzodiazepine binding site (BDZ-bs) of the GABA(A) receptor complex. Since 1989 onwards our laboratories established that some natural flavonoids were ligands for the BDZ-bs which exhibit medium to high affinity in vitro and anxiolytic activity in vivo. Further research resulted in the production of synthetic flavonoid derivatives with increased biochemical and pharmacological activities. The currently accepted receptor/pharmacophore modelof the BDZ-bs (Zhang, W.; Koeler, K. F.; Zhang, P.; Cook, J. M. Drug Des. Dev. 1995, 12, 193) accounts for the general requirements that should be met by this receptor for ligand recognition. In this paper we present a modelpharmacophore which defines the characteristics for a ligand to be able tointeract and bind to a flavone site, in the GABA(A) receptor, closely related to the BDZ-bs. A model of a flavone binding site has already been described (Dekermendjian, K.: Kahnberg, P.: Witt, M. R.: Sterner, O.: Nielsen, M.: Liljerfors, T. J. Med. Chem. 1999, 42, 4343). However, this alternative model is based only on graphic superposition techniques using as template anon-BDZ agonist. In this investigation all the natural and synthetic flavonoids found to be ligands for the BDZ-bs have been compared with the classical BDZ diazepam. A QSAR regression analysis of the parameters that describe the interaction demonstrates the relevance of the electronic effects for the ligand binding, and shows that they are associated with the negatively charged oxygen atom of the carbonyl group of the flavonoids and with the nature of the substituent in position 3'. (C) 2001 Elsevier Science Ltd. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 28/01/20 alle ore 14:50:59