Recently, it was found that annelation of six- or seven-mambered ring at 7,8-position of theophylline change the profile of its CNS activity in comparison to the mother compound (theophylline). Instead of stimulating activity they showed sedative, hypothermic, analgesic and neuroleptic-like properties [1]. In our earlier study a series of arylpiperazinylalkyl derivatives with complex terminal part based on the purine moiety were synthesized. Compounds with pyrimido[2,1-f]theophylline fragment showed a significant activity for 5-HT_1A receptors and diversified pharmacological profile [2-4].

To study the influence of chemical modyfication of the purine fragment on the CNS receptors affinity, we have synthesized new arylpiperazinylalkyl derivatives of imidazo[2,1-f]theophylline. The modyfication of pattern structure were made at 7-position (methyl or phenyl moiety), at alkilene spacer (3-4 methylene units) and kind of the substituent at phenyl ring of the arylpiperazinyl moiety (Scheme). The newly synthesized compounds exhibit multireceptor profile as potent 5-HT_1A, α₁ and D₂ receptor ligands. The most potent ligands were tested in vivo to evaluate their functional CNS activity and selected compounds were evalueted for their anxiolytic and antidepressant activity. The results indicated that the tricyclic teophylline derivatives linked with arylpiperazinylalkyl moiety are interesting class of compounds for searching a new CNS agents with antidepressant/anxiolytic an neuroleptic like activity.

[1]. Pawłowski, M.; Drabczyńska, A.; Gorczyca, M.; Malec, D.; Modzelewski, J. Pharmazie 1995, 50, 453-455.

[2]. Chojnacka-Wójcik, E.; Kłodzińska, A.; Drabczyńska, A.; Pawłowski, M.; Charakchieva-Minol, S.; Chłoń, G.; Gorczyca, M. Eur. J. Med. Chem. 1995, 30, 587-592.

[3]. Pawłowski, M.; Katlabi, J.; Drabczyńska, A.; Duszyńska, B.; Charakchieva-Minol, S.; Dereń-Wesołek, A.; Tatarczyńska, E.; Chojnacka-Wójcik, E.; Mokrosz, M. J.; Bojarski, A. J. Eur. J. Med. Chem. 1999, 34, 167-175.

[4]. Pawłowski, M.; Drabczyńska, A.; Katlabi, J.; Gorczyca, M.; Malec, D.; Modzelewski, J. Eur. J. Med. Chem. 1999, 34, 1085-1091.

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