Synthesis of 2-semicarbazonomethyl-4,5-methylenedioxyphenylacetic acids as anticonvulsant agents Nicola Micale a, *, Maria Zappalà a , Giuseppe Zuccalà a , Frank S. Menniti b , Guido Ferreri c , Giovambattista De Sarro c , Silvana Grasso 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 Received 27 September 2004; received in revised form 25 November 2004; accepted 27 November 2004 Abstract A series of 2-semicarbazonomethyl-4,5-methylenedioxyphenylacetic acids (12–19) were synthesized and tested as anticonvulsant agents in DBA/2 mice against sound-induced seizures and the results compared to those previously reported for the corresponding methyl esters (4-11). The new compounds possess anticonvulsant properties lower than those of 4–11, but, in some instances, comparable to that of GYKI 52466, a well-known noncompetitive AMPA receptor antagonist. © 2005 Elsevier SAS. All rights reserved. Keywords: 4,5-Methylenedioxyphenylacetic acids; Anticonvulsant activity; AMPA antagonists 1. Introduction Epilepsy, one of the most frequent neurological afflictions in man characterized by excessive temporary neuronal dis- charges resulting in uncontrolled convulsion, requires spe- cial medical attention. Although several new anticonvulsants are already in clinical use, some types of seizures are still not adequately treated with current therapy. Toxicity, intoler- ance, and lack of efficacy for certain types of seizure are some of the limitations of the current medications [1]. Drugs effective against the most common forms of epilep- tic seizures appear to work by limiting the sustained repeti- tive firing of a neuron by one of the following mechanisms: (i) enhancement of GABA-mediated synaptic inhibition, (ii) stabilization of the inactivated state of voltage-operated Na + channels, (iii) inactivation of voltage-activated Ca 2+ chan- nels. Considerable interest has recently been focused on antago- nists of the ionotropic glutamate receptors (NMDA, AMPA and KA) having significant anticonvulsant activity thus pro- viding the basis for an extensive research in this area. GYKI 52466 (1, 1-(4-aminophenyl)-4-methyl-7,8- methylenedioxy-5H-2,3-benzodiazepine) and its analogues such as GYKI 53655 (2)(Fig. 1), acting as noncompetitive antagonists of the AMPA receptors [2,3], displayed potent anticonvulsant properties [4,5] and this induced growing inter- est on 2,3-benzodiazepine derivatives. Since some time our research group is involved in the search of new noncompetitive AMPA receptor antagonists containing the 2,3-benzodiazepine skeleton [6–8]. Based on the anticonvulsant properties of the previously described [7] 1-(4-aminophenyl)-3,5-dihydro-3-N-methyl- carbamoyl-7,8-methylenedioxy-4H-2,3-benzodiazepin-4- one (3), we recently designed and tested [9,10] a series of alkyl esters of 4,5-methylendioxyphenyl acetic acid (e.g., 4–11) bearing an N-alkyl-(thio)semicarbazonomethyl moi- ety at position 2, which may be envisaged as “open models” of reference compound 3 (Fig. 1). Within this series of deriva- tives, methyl ( Z)-2-[(4-aminophenyl)-(4-methylsemi- carbazono)-methyl]-4,5-methylenedioxyphenyl-acetate 11 proved to be the most active compound. It displayed an anti- convulsant activity slightly higher than that of its parent 3 and 5-fold higher than that shown by reference compound GYKI 52466. * Corresponding author. E-mail address: nmicale@pharma.unime.it (N. Micale). Il Farmaco 60 (2005) 231–235 http://france.elsevier.com/direct/FARMAC/ 0014-827X/$ - see front matter © 2005 Elsevier SAS. All rights reserved. doi:10.1016/j.farmac.2004.11.012