On account of complex and unclear mechanisms underlying the onset and development of epilepsy, in search for new anticonvulsant agents, various chemical structures and many targets are taken into consideration. It has been proved that γ-hydroxybutyric acid (GHB) as well as its cyclic analogue, γ-butyrolactone (GBL), both influence the gabaergic transmission, which plays a pivotal role in physiological and pathological processes in the central nervous system (CNS), including epilepsy. In recent years several α-substituted butyramides have been approved as the antiepileptic drugs (levetiracetam, breviracetam), and other related structures are in early clinical development (harkoseride) [1, 2].

This work is a part of physicochemical and pharmacological studies of N-substituted amides of α-arylalkylamino-GHB with expected anticonvulsant activity and gabaergic mechanism of action [3]. With the aim to determine the influence of the α-arylalkylamine moiety on anticonvulsant activity, two series of compounds, derivatives of α-substituted GBL and GHB were synthesized. These compounds contain aryalkylamine substituents with modified lipophilic phenyl ring or alkylamine groups (aliphatic or cyclic) in the α-position.

Preliminary anticonvulsant in vivo tests of these compounds, i.e. the maximal electroshock test, the subcutaneous metrazole induced seizures, and the rotorod toxicity assay on mice were employed.

1. Malawska B. Curr. Topics Med. Chem. 2005, 5, 69-86.
2. Löscher, W.; Schmidt, D., Epilepsy Res., 2004, 60, 77-159.
3. B. Malawska, K. Kulig, A. Śpiewak, J. P. Stables, Bioorg. Med. Chem., 2004, 12, 625-632.

Acknowledgements: We thank Dr J.P. Stables for anticonvulsant testing and to the Anticonvulsant Screening Project, National Institute of Neurological Disorders and Stroke, Bethesda, USA.

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