Synthesis of 5-substituted 7,9-dihydro-8H-[1,3]dioxolo[4,5-h][2,3]benzodiazepin-8-ones as anticonvulsant agents

Maria Zappalà; Nicola Micale; Silvana Grasso; Frank S. Menniti; Giovambattista De Sarro; Carlo De Micheli

doi:10.3998/ark.5550190.0005.518

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Synthesis of 5-substituted 7,9-dihydro-8H-[1,3]dioxolo[4,5-h][2,3]benzodiazepin-8-ones as anticonvulsant agents

Maria Zappalà; Nicola Micale; Silvana Grasso; Frank S. Menniti; Giovambattista De Sarro; Carlo De Micheli

Volume 2004, Issue 5, Commemorative Issue in Honor of Prof. Vincenzo Tortorella on the occasion of his receiving Fuori Ruolo status, pp. 196-203

DOI: http://dx.doi.org/10.3998/ark.5550190.0005.518

Paper ID: VT-1018LP

Received on 2003-12-19; Accepted on 2004-03-05; Published on 2004-03-10

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Issue in Honor of Prof. Vincenzo Tortorella ARKIVOC 2004 (v) 196-203 Synthesis of 5-substituted 7,9-dihydro-8H-[1,3]dioxolo[4,5-h][2,3]benzodiazepin-8-ones as anticonvulsant agents Maria Zappalà,a Nicola Micale,a, Silvana Grasso,a,* Frank S. Menniti,b Giovambattista De Sarro,c and Carlo De Michelid a Dipartimento Farmaco-Chimico, Università di Messina, viale Annunziata, 98168 Messina, Italy, b Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA, c Dipartimento di Medicina Sperimentale e Clinica, Università di Catanzaro, Via T. Campanella, 88100 Catanzaro, Italy, d Istituto di Chimica Farmaceutica, Università di Milano, viale Abruzzi, 42, 20131 Milano, Italy E-mail: grasso@pharma.unime.it Dedicated to Professor Vincenzo Tortorella on the occasion of his “Fuori Ruolo” status (received 19 Dec 03; accepted 05 Mar 04; published on the web 10 Mar 04) Abstract 5-(4-Aminobenzyl)-7,9-dihydro-8H-[1,3]dioxolo[4,5-h][2,3]benzodiazepin-8-one (3) and 7,9dihydro- 5-[2-(pyridin-2-yl)-vinyl]-8H-[1,3]dioxolo[4,5-h][2,3]benzodiazepin-8-one (4) were synthesized and screened as anticonvulsant agents in DBA/2 mice against sound-induced seizures. The new compounds are provided with anticonvulsant properties even if ED50 values are lower than those of prototype 5-(4-aminophenyl)-7,9-dihydro-8H-[1,3]dioxolo[4,5h][ 2,3]benzodiazepin-8-one (2) and of GYKI 52466 (1), a well-known noncompetitive AMPA receptor antagonist. Binding assays and functional tests were performed to evaluate the affinity for AMPA and kainate receptors. Keywords: 7,9-Dihydro-8H-[1,3]dioxolo[4,5-h][2,3]benzodiazepin-8-ones, anticonvulsant activity Introduction Ionotropic glutamate receptors (iGluRs) are the major excitatory neurotransmitter receptor proteins in the mammalian brain.1,2 As a class of membrane proteins, iGluRs are composed of subunits that span the membrane to form a small pore or channel, which is gated by glutamate, a neurotransmitter. When glutamate is released from a presynaptic neuron and binds to a postsynaptic glutamate receptor, the receptor rapidly changes its conformation and transiently forms an open ion channel, thus resulting in a change of the postsynaptic membrane potential. A postsynaptic potential of sufficient strength triggers an action potential, which will in turn ISSN 1424-6376 Page 196 ©ARKAT USA, Inc 0