7,8-Methylenedioxy-4H-2,3-benzodiazepin-4-ones as novel AMPA receptor antagonists

Sarro, Angela De; Sarro, G. De; Gitto, Rosaria; Grasso, Silvana; Micale, Nicola; Quartarone, Silvana; Zappalà, Maria

doi:10.1016/s0960-894x(98)00148-6

Cited by 41 publications

(36 citation statements)

References 17 publications

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“…[16][17][18][19][20] We used the prototypical AMPAR negative modulator GYKI 52466 (1) as lead compound and planned a series of modifications on the 2,3-benzodiazepine skeleton to obtain more potent, less toxic, and longer lasting bioactive molecules (Figure 1). [21][22][23][24] The compounds designed were prepared by conventional procedures and a solid-phase approach.…”

Section: Resultsmentioning

confidence: 99%

Combined Strategies for the Discovery of Ionotropic Glutamate Receptor Antagonists

et al. 2009

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New glutamate receptor ligands: This review describes the discovery of rationally designed AMPA and NMDA receptor antagonists, some of which have been proven to be highly potent anticonvulsant and neuroprotective agents.This review summarizes the results of our research group engaged in the development of new glutamate receptor ligands. Chemical and biological studies of several active molecules have been carried out. In particular, extensive work has addressed the identification of antagonists of AMPA and NMDA receptor subtypes using a combination of computational strategies. Innovative synthetic pathways have been used and small libraries of new molecules prepared. In vitro and in vivo tests were performed, and some compounds proved to be highly potent anticonvulsant and neuroprotective agents.

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Section: Resultsmentioning

confidence: 99%

Combined Strategies for the Discovery of Ionotropic Glutamate Receptor Antagonists

et al. 2009

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“…At present, compound IV (Fig. 6) is one of the most potent 2,3-benzodiazepine analogues reported with anticonvulsant activity against audiogenic seizures in DBA/2 mice (CHIMIRRI et al 1997;DE SARRO et al 1998).…”

Section: Therapeutic Potential Of Amp a And Kainate Receptor Ligandsmentioning

confidence: 97%

Glutamate Receptor Ion Channels: Activators and Inhibitors

Jane¹,

Tse²,

Skifter³

et al. 2000

Pharmacology of Ionic Channel Function: Activators and Inhibitors

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The classification of excitatory amino acid (EAA) receptors into N-methyl-oaspartic acid (NMDA) and non-NMDA receptors was based mainly on the discovery of selective agonists and antagonists (for a review see WATKINS and EVANS 1981). Thus the selective NMDA receptor antagonist, o-aaminoadipate blocked responses due to NMDA but not those due to quisqualate or kainate in the frog and rat spinal cord. Evidence for more than one type of non-NMDA receptor came from the observation that responses due to quisqualate but not those due to kainate are depressed by L-glutamic acid diethyl ester (GDEE) (McLENNAN and LOOGE 1979; while responses to kainate can be selectively antagonized by y"oglutamylglycine (rDGG) . In addition, receptors present on dorsal root fibers were shown to be sensitive to kainate but not quisqualate ). These observations resulted in the classification of EAA receptors into NMDA, quisqualate and kainate receptors. Such receptors are linked to ionic fluxes and are now known as ionotropic glutamate receptors (iGluRs) as distinct from the more recently discovered metabotropic glutamate receptors (mGluRs) linked to G-protein coupled metabolic changes (CONN and PIN 1997). The isoxazole analogue, (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) was reported to be more selective for the quisqualate type of iGluR than quisqualate itself (KROGSGAARO-LARSEN et al. 1980 and this led to this ionotropic receptor being renamed the AMPA receptor to avoid confusion with quisqualate-activated mGluRs (MONAGHAN et al. 1989;). Molecular biology has identified a large number of subtypes of both iGluRs and mGluRs.Progress in defining the role of EAA receptors in CNS function has also followed the development of receptor-selective antagonists. With the availability of NMDA receptor antagonists, it was possible to demonstrate a role of NMDA receptors in polysynaptic responses in the vertebrate spinal cord EVANS et al. 1979) and in hippocampal long term potentiation (COLLINGRIDGE et al. 1983;HARRIS et al. 1984

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“…10 The results are compared with those previously reported for derivative 2 and reference compound 1 (Table 1). 7,8 As shown in Table 1, compound 4 possesses anticonvulsant properties lower than those of prototype 2 as well of lead compound 1 whereas derivative 3, even if unable to prevent the clonic phase of the audiogenic seizures, significantly reduces the tonic phase of the seizures; its ED 50 value is comparable to that of GYKI 52466. from the corresponding binding site of the AMPA receptor complex ( Table 2). The inhibition of [ 3 H]CP-526,427 specific binding (3 nM) to rat forebrain membranes was evaluated as previously described.…”

Section: Pharmacologymentioning

confidence: 98%

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

Zappalà¹,

Micale²,

Grasso³

et al. 2004

Arkivoc

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7,8-Methylenedioxy-4H-2,3-benzodiazepin-4-ones as novel AMPA receptor antagonists

Cited by 41 publications

References 17 publications

Combined Strategies for the Discovery of Ionotropic Glutamate Receptor Antagonists

Combined Strategies for the Discovery of Ionotropic Glutamate Receptor Antagonists

Glutamate Receptor Ion Channels: Activators and Inhibitors

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

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