The incomplete information on the pathogenesis of human epilepsy and the complex mechanism of action of majority antiepileptic drugs makes it difficult to use rational methodologies of discovery that are based on three-dimensional structure of biological target. Thus the most useful for the design of new anticonvulsants are ligand-based approaches that rely on the use of different pharmacophores established through the analysis of structural characteristics of clinically effective antiepileptic drugs (AEDs) as well as other anticonvulsant active compounds [1]. The two past decades have demonstrated many attempts to identify the structural features of compounds crucial for anticonvulsant activity. As a result it was proved that one of the important core fragments is defined by nitrogen heteroatomic system, usually imide or lactam, at least of one carbonyl group and phenyl or alkyl groups attached to the heterocyclic system [2,3].

The previous studies from our laboratory have demonstrated potent anticonvulsant activity in groups of 1-[(4-phenyl- piperazin-1-yl)-alkyl]-3-phenyl-pyrrolidine-2,5-diones [4,5]. These molecules were effective mainly in the maximal electroshock test (MES) which an animal model of human generalized tonic-clonic epilepsy. As a continuation of our systematic SAR analysis in the present studies we have obtained a series of 1-[(4-substituted-piperazin-1-yl)-alkyl]-3-methyl-3-(2-methylpropyl)pyrrolidine-2,5-diones. These molecules have been designed as analogues of respective, active 3-phenyl-pyrrolidine-2,5-diones. The structures of compounds synthesized are shown in Fig. 1.

Fig. 1.

All the compounds were evaluated for their anticonvulsant activity and neurotoxic properties within the Antiepileptic Drug Development (ADD) Program (Epilepsy Branch, Neurological Disorders Program, National Institute of the Neurological and Communicative Disorders and Stroke (NINCDS), Rockville, USA) [6]. Because several molecules can be regarded as long-chain arylpiperazines (LCAPs) in the current studies the affinities for 5-HT_1A and 5-HT₇ receptor subtypes have been assessed.

We are pleased to acknowledge the generous financial support of this work by the grant of the Minister Committee for Scientific Research, Poland (Grant NoN405 298536).

References:

[1] Khan, H.N.; Kulsoom, S.; Rashid, H. Epilepsy Res. 2012, 98, 62.

[2] Wong, M.G.; Defina, J.A.; Andrews, P.R. J. Med. Chem. 1986, 29, 562.

[3] Tasso, S.M.; Bruno-Blanch, L.E.; Moon, S.C.; Estiú, G.L. J. Mol. Struct. 2000, 504, 229.

[4] Obniska, J.; Kamiński, K.; Skrzyńska, D.; Pichór, J. Eur. J. Med. Chem. 2009, 44, 2224.

[5] Obniska, J.; Kopytko, M.; Zagórska, A.; Chlebek, I.; Kamiński, K. Arch. Pharm. 2010, 343, 333.

[6] Kupferberg H. J. Epilepsia 1989, 30 (suppl.), 51.

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