Molecular modeling and QSAR analysis of the interaction of flavone derivatives with the benzodiazepine binding site of the GABA(A) receptor complex

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.