New 7,8-ethylenedioxy-2,3-benzodiazepines as noncompetitive AMPA receptor antagonists Maria Zappala `, a Alessia Pellicano `, a Nicola Micale, a, * Frank S. Menniti, b Guido Ferreri, c Giovambattista De Sarro, c Silvana Grasso a and Carlo De Micheli d a Dipartimento Farmaco-Chimico, Universita ` di Messina, Viale Annunziata 98168, Messina, Italy b Pfizer Global Research and Development, Groton, CT, USA c Dipartimento di Medicina Sperimentale e Clinica, Universita ` di Catanzaro, Via T. Campanella 88100, Catanzaro, Italy d Istituto di Chimica Farmaceutica, Universita ` di Milano, Viale Abruzzi 42, 20121 Milano, Italy Received 13 June 2005; revised 9 September 2005; accepted 12 September 2005 Available online 10 October 2005 Abstract—A series of 1-aryl-3,5-dihydro-7,8-ethylenedioxy-4H-2,3-benzodiazepin-4-ones 2a–f, were synthesized and screened as anticonvulsant agents in DBA/2 mice against sound-induced seizures. The new compounds display anticonvulsant properties although the ED 50 values are higher than those of prototypes 1-aryl-3,5-dihydro-7,8-methylenedioxy-4H-2,3-benzodiazepin-4-ones (1) and GYKI 52466, well-known noncompetitive AMPA receptor antagonists. Functional tests were performed to evaluate the antagonistic activity at the AMPA and kainate receptors. Ó 2005 Elsevier Ltd. All rights reserved. There is increasing evidence of the potential therapeutic utility of AMPA receptor antagonists in the treatment of several neurodegenerative disorders, including stroke and epilepsy. The discovery of GYKI 52466 as the pro- totype of noncompetitive AMPA antagonists endowed with anticonvulsant and neuroprotective properties, in- duced wide-ranging research activities focused on 2,3- benzodiazepines. 1 Highly active analogs of GYKI 52466 (Fig. 1) have been found among its 3,4-dihydro-3-N-methylcarbamoyl (GYKI 53655) and 3,4-dihydro-3-acetyl (GYKI 53405) derivatives. 2 In particular, the 4-R enantiomer of GYKI 53405 was chosen as drug candidate and is now in clin- ical investigation as LY 300164 (talampanel). 3 We have previously investigated 4 a new series of 1-aryl- 3,5-dihydro-7,8-methylenedioxy-4H-2,3-benzodiazepin- 4-ones, e.g., 1a, and their 3-N-alkylcarbamoyl derivatives, e.g., 1b–1c, which have been shown to possess remarkable anticonvulsant properties and are endowed with a higher potency compared to GYKI 52466. In this context we noticed that substitution of the imi- nohydrazone portion of the diazepine nucleus of GYKI 52466 by the iminohydrazide moiety as well as the pres- ence of the substituent appended at the N-3-position positively affect the anticonvulsant activity. Further- more, we demonstrated that these derivatives compete with GYKI 52466 for the same allosteric binding site of the AMPA receptors. 5 As an extension of our studies on the structure–activity relationships of this set of derivatives, we designed and screened for anticonvulsant activity new 3,5-dihydro- 7,8-ethylenedioxy-4H-2,3-benzodiazepin-4-ones 2a–c, in order to check how the substitution of the dioxole 0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2005.09.029 Keywords: 3,5-Dihydro-7,8-ethylenedioxy-4H-2,3-benzodiazepin-4- ones; Anticonvulsant activity; AMPA receptor antagonists. * Corresponding author. Tel.: +39 090 6766466; fax: +39 090 355613; e-mail: nmicale@pharma.unime.it O O N N CH 3 N H 2 O O N N CH 3 N H 2 O R O O NR N O N H 2 GYKI 52466 GYKI 53655, R=NHCH 3 GYKI 53405, R=CH 3 1a, R=H, 1b, R=CONHCH 3 1c, R=CONHC 2 H 5 Figure 1. Bioorganic & Medicinal Chemistry Letters 16 (2006) 167–170