There is growing evidence that serotoninergic neurotransmission modulates a wide variety of experimentally induced seizures and is involved in the enhanced seizure susceptibility observed in some genetically-epilepsy-prone rats GEPR_S [1]. The anti-seizure activity many of 5-HT receptor ligands would indicate that an anticonvulsant effect can be obtained not only by the GABA and glutamate systems but also by potentiating serotoninergic neurotransmission [2]. Moreover, serotonin may play a role in the mechanism of action some antiepileptic drugs such as carbamazepine which increase extracellular 5-HT at anticonvulsant doses in GEPR_S [3]. On the other hand, it has also been shown that fluoxetine, a selective serotonin reuptake inhibitor (SSRI_S) exhibited anticonvulsant effect both in the experimental animals and in man [4].
Based on these data, in the course of our research on development new potentially anticonvulsant agents as well as potent 5-HT_1A and 5-HT_2A receptor ligands, we designed and synthesized a series of long chain arylpiperazines (LCAPs) containing as a cyclic amide fragments 2-azaspiro[4.4]nonane- and [4.5]decane-1,3-dione moiety [5, 6].
Among these compounds several anticonvulsant active derivatives were found, on the other hand some of them were high 5-HT_1A and 5-HT_2A receptors ligands (K_i ranged from 3.1 nM to 94 nM and 29 nM to 82 nM respectively). According to the results obtained, we can suppose that anticonvulsant activity of compounds described above, may resulte from activation of 5-HT_1A or 5-HT_2A receptors but further studies are required to confirm this hypothesis.

References

1. Filakovszky J., Gerber K., Bagdy G. A. Neurosci. Lett. 261 (1999) 89-92.
2. Stean T. O., Atkins A. R., Heidbreder C. A., Quinn L. P., Trail B. K., Upton N.
Br. J. Pharmacol. 144 (2005) 628-635.
3. Dailey J. W., Reith M. E., Yan Q. S., Li M. Y., Jobe P. C. Neurosci. Lett. 227 (199713-16.
4. Jobe P. C. Epilepsy Behav. 4 (2003) S14-S24.
5. Obniska J., Kołaczkowski M., Charakchieva-Minol S., Nędza K., Dybała M., Bojarski A. Pharmacol. Rep. 57 (2005) 336-344.
6. Obniska J., Kołaczkowski M., Bojarski A., Duszyńska B. Eur. J. Med. Chem. submitted(2006).

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