Design of 1-substituted 2-arylmethyl-4,5-methylenedioxybenzene derivatives as antiseizure agents Nicola Micale, a Giovambattista De Sarro, b Guido Ferreri, b Maria Zappal a, a Silvana Grasso, a Giulia Puia c and Carlo De Micheli d, * a Dipartimento Farmaco-Chimico, Universit a di Messina, Viale Annunziata 98168, Messina, Italy b Dipartimento di Medicina Sperimentale e Clinica, Universit a di Catanzaro, Via T. Campanella 88100, Catanzaro, Italy c Dipartimento di Scienze Farmaceutiche,Universit a di Modena, Via dei Campi 183, 41100 Modena, Italy d Istituto di Chimica Farmaceutica, Universit a di Milano, Viale Abruzzi 42, 20121 Milan, Italy Received 12 December 2003; accepted 7 April 2004 Available online 18 May 2004 Abstract—A series of 1-substituted 2-[(4-aryl)-methyl]-4,5-methylenedioxybenzene derivatives (13–25), structurally related to model compound 5 (2-[(4-aminophenyl)-(4-methylsemicarbazono)-methyl]-4,5-methylenedioxyphenylacetic acid methyl ester), were syn- thesized and tested as anticonvulsant agents in DBA/2 mice against sound-induced seizures. The new compounds possess anti- convulsant properties lower than those of prototype 5 but, in some instances, comparable to that of GYKI 52466, a well-known noncompetitive AMPA receptor antagonist. Ó 2004 Elsevier Ltd. All rights reserved. 1. Introduction Epilepsies are common neurological disorders, affecting approximately 2.5 million people solely in the United States. Epileptic seizures often cause transient impairment of consciousness, leaving the individual at risk of bodily harm. Therapy is symptomatic in that available drugs inhibit seizures, but they neither affect prophylaxis nor cure the cause. Compliance with medication is a major problem, due to the need of a long-term therapy, which is quite often associated with unwanted side effects. 1 Drugs effective against the most common forms of epi- leptic seizures, appear to work by limiting the sustained repetitive firing of a neuron by one of the following mechanisms: (i) enhancement of GABA-mediated syn- aptic inhibition, (ii) stabilization of the inactivated state of voltage-operated Na þ channels, (iii) inactivation of volt- age-activated Ca 2þ channels. Considerable interest has lately been focused on antagonists of the ionotropic glu- tamate receptors (NMDA, AMPA, and KA) having sig- nificant anticonvulsant activity thus providing the basis for an extensive research in this area. As a matter of fact, a number of 2,3-benzodiazepine derivatives, that is GYKI 52466 (1) and GYKI 53655 (2) (Fig. 1), acting as non- competitive antagonists of the AMPA receptors, 2 dis- played potent anticonvulsant properties 3;4 and behaved as neuroprotective agents in focal and global ischemia. 5 As part of a program aimed at identifying potent and selective AMPA receptor antagonists, we have previously reported 6;7 an investigation on the anticonvulsant activ- ity of a series of 1-aryl-3,5-dihydro-7,8-methylenedioxy- 4H-2,3-benzodiazepin-4-ones, for example, 3, and their 3-N-alkylcarbamoyl derivatives, for example, 4 (Fig. 1), which are structural analogues of 1 and 2, respectively. Compounds 3–4 proved to be roughly 2–3-fold more potent than GYKI 52466 and were provided with a R N H 2 CH 3 N N O O O O NR N O N H 2 O O N H 2 N N H O NHMe O OMe 1, GYKI 52466 3,4-Δ 2, GYKI 53655 3,4-dihydro, R = CONHMe 3, R = H 4, R = CONHMe 5 Figure 1. * Corresponding author. Tel.: +39-02-50317538; fax: +39-02-503175- 74; e-mail: carlo.demicheli@unimi.it 0968-0896/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2004.04.015 Bioorganic & Medicinal Chemistry 12 (2004) 3703–3709