Benzoazepine derivative as potent antagonists of the glycine binding site associated to the NMDA receptor
2003; Elsevier BV; Volume: 58; Issue: 9 Linguagem: Inglês
10.1016/s0014-827x(03)00166-6
ISSN1879-0569
AutoresRomano Di Fabio, Fabrizio Micheli, Davide Baraldi, Barbara Bertani, Nadia Conti, Giovanna Dal Forno, Aldo Feriani, Daniele Donati, Carla Marchioro, Tommaso Messeri, Andrea Missio, Alessandra Pasquarello, Giorgio Pentassuglia, Domenica A. Pizzi, Stefano Provera, Anna M. Quaglia, Fabio Maria Sabbatini,
Tópico(s)Epilepsy research and treatment
ResumoA series of benzoazepine derivatives, bearing suitable substituents at the C-3 position, was designed and evaluated by superimposition with the pharmacophore model of the glycine binding site. To fully explore the SAR of this class of compounds and to allow the preparation of new different compounds at the C-3 position, appropriate synthetic routes were set up. The benzoazepines were evaluated in terms of in vitro affinity using [3H]glycine binding assay and in vivo potency by inhibition of convulsions induced by N-methyl-d-aspartate (NMDA) in mice. This further analysis confirmed the preliminary results previously reported and that compound 27 is the most promising compound (Ki=32 nM, ED50=0.09 mg/kg, i.v.) in this series. Significant neuroprotective effect was observed after both pre- and post-ischaemia administration in the MCAo model. In particular, after post-ischaemia administration, it was found to be still effective when the administration was delayed up to 6 h after occlusion of the middle cerebral artery.
Referência(s)