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
A large number of structurally different classes of ligands, many of them s
haring the main characteristics of the benzodiazepine (BDZ) nucleus, are ac
tive in the modulation of anxiety, sedation, convulsion, myorelaxation, hyp
notic 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 flavonoid
s were ligands for the BDZ-bs which exhibit medium to high affinity in vitr
o and anxiolytic activity in vivo. Further research resulted in the product
ion of synthetic flavonoid derivatives with increased biochemical and pharm
acological activities. The currently accepted receptor/pharmacophore model
of the BDZ-bs (Zhang, W.; Koeler, K. F.; Zhang, P.; Cook, J. M. Drug Des. D
ev. 1995, 12, 193) accounts for the general requirements that should be met
by this receptor for ligand recognition. In this paper we present a model
pharmacophore which defines the characteristics for a ligand to be able to
interact and bind to a flavone site, in the GABA(A) receptor, closely relat
ed to the BDZ-bs. A model of a flavone binding site has already been descri
bed (Dekermendjian, K.: Kahnberg, P.: Witt, M. R.: Sterner, O.: Nielsen, M.
: Liljerfors, T. J. Med. Chem. 1999, 42, 4343). However, this alternative m
odel is based only on graphic superposition techniques using as template a
non-BDZ agonist. In this investigation all the natural and synthetic flavon
oids found to be ligands for the BDZ-bs have been compared with the classic
al BDZ diazepam. A QSAR regression analysis of the parameters that describe
the interaction demonstrates the relevance of the electronic effects for t
he ligand binding, and shows that they are associated with the negatively c
harged oxygen atom of the carbonyl group of the flavonoids and with the nat
ure of the substituent in position 3'. (C) 2001 Elsevier Science Ltd. All r
ights reserved.