3,5-Dihydro-4H-2,3-benzodiazepine-4-thiones:  A New Class of AMPA Receptor Antagonists

Chimirri, A., De Sarro, G., De Sarro, A., Gitto, R., Quartarone, S., Zappalà, M., Constanti, A. and Libri, V. (1998) 3,5-Dihydro-4H-2,3-benzodiazepine-4-thiones:  A New Class of AMPA Receptor Antagonists. Journal of Medicinal Chemistry, 41 (18). pp. 3409-3416. 10.1021/jm9800393.

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DOI: 10.1021/jm9800393


Synthesis and evaluation of anticonvulsant activity of a series of 2,3- benzodiazepin-4-ones (2) chemically related to 1-(4'-aminophenyl)-4-methyl- 7,8-(methylenedioxy)-5H-2,3-benzodiazepine (1, GYKI 52466) have been reported in our recent publications. Compounds 2 manifested marked anticonvulsant properties acting as 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptor antagonists. In an attempt to better define the structure-activity relationships (SAR) and to obtain more potent and selective anticonvulsant agents, 1-aryl-3,5-dihydro-4H-2,3-benzodiazepine-4- thiones 3 were synthesized from the corresponding isosteres 2. The evaluation is reported of their anticonvulsant effects, both in the audiogenic seizures test with DBA/2 mice and against the maximal electroshock- and pentylenetetrazole-induced seizures in Swiss mice. New derivatives 3 showed higher potency, less toxicity and longer-lasting anticonvulsant action than those of the parent compounds 2 in all tests employed analogous to derivatives 2, new compounds 3 do not affect the benzodiazepine receptor (BZR) while they do antagonize AMPA-induced seizures; their anticonvulsant activity is reversed by pretreatment with aniracetam but not with flumazenil, thus suggesting a clear involvement of AMPA receptors. Electrophysiological data indicate a noncompetitive blocking mechanism at the AMPA receptor sites for 3i, the most active of the series and over 5-fold more potent than 1.

Item Type:Article
Departments, units and centres:Department of Pharmacology > Department of Pharmacology
ID Code:3291
Journal or Publication Title:Journal of Medicinal Chemistry
Deposited By:Library Staff
Deposited On:25 May 2012 09:08
Last Modified:25 May 2012 09:08

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