In recent years there have been a lot of published articles aimed at creating a single hybrid molecule that possesses both 5-HT_1A antagonism and serotonin reuptake inhibition [1-4]. Such a molecule could prove to be a better rapidly acting antidepressant than selective serotonin reuptake inhibitors (SSRIs), which are currently used in the therapy of depression [5].

In the course of searching for the new potential antidepressants, which block 5-HT_1A receptor and inhibit serotonin reuptake, series of arylpiperazinylalkyl containing 5-aryl-imidazolidine-2,4-dione moiety were synthesized. Then their influence on central serotonergic transmission was examined in a different pharmacological tests. In the radioligand studies the affinity towards central nervous system receptors (5-HT_1A, 5-HT_2A and α₁) and serotonin transporter were evaluated. For selected compounds, which have shown specially promising properties in in vitro tests, their anxiolytic and antidepressant activities were investigated in the four-plate test, in the forced swimming test and in the locomotor activity test in mice.

In order to describe the interaction mode of the investigated compounds with 5-HT_1A serotonin receptor, in silico studies were carried out, comprising automated docking of selected compounds to the molecular model of 5-HT_1A receptor. Furthermore the lipophilic character of the compounds (a crucial physicochemical factor for potential CNS activity) was also evaluated by use of RP-TLC and computational methods.

Acknowledgement: The authors thank to Polish Ministry of Science and Higher Education for financial support (grant No 2P05F04329).

References:
[1] R. E. Mewshaw, K. L. Meagher, P. Zhou, D. Zhou, X. Shi et al.: Bioorg. Med. Chem. Lett., 12, 307, 2002
[2] K. Takeuchi, T. J. Kohn, N. A. Honigschmidt, V. P. Rocco et al.: Bioorg. Med. Chem. Lett., 16, 2347, 2006
[3] T. Heinrich, H. Bottcher, K. Schiemann, G. Holzemann, et al.: Bioorg. Med. Chem., 12, 4843, 2004
[4] P. J. Lovell, F. E. Blaney, C. J. Goodacre, C. M. Scott et al.: Bioorg. Med. Chem. Lett., 17, 1033, 2007
[5] D. A. Evrard, P. Zhou, S.Y. Yi, D. Zhou, D. L. Smith et al.: Bioorg. Med. Chem. Lett., 15, 911, 2005

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