Long chain arylpiperazines have been found as serotonin receptor ligands in particular 5-HT_1A and 5-HT_2A ones. Their general chemical structure contains: an alkyl chain (2-4 methylene units) attached to the N4 atom of the piperazine moiety, and terminal fragment: amide or an imide. The significance of the terminal part in ligand-receptor interactions has been the subject of many structure-activity relationships studies [1]. In our earlier study a series of arylpiperazinylalkyl derivatives with a complex terminal part based on the purine moiety had been synthesized. For compounds with pirymido[2,1-f]theophylline fragment high or very high receptor affinity and diversified pharmacological profile were observed [2-4]. The most potent for serotonin receptors were compounds with double bonds at anneleted six member ring at 7,8 position of the theophylline [2-4]. On the basis of the above data we have synthesised the new tricyclic theophylline with five member ring (Fig 1 ) to study the influence of ring size and the presence of double bond, the kind of the substituent at N4 position of arylpiperazine moiety on serotonin receptors activity.

Fig 1.

The newly synthesized compounds in a form of water-soluble hydrochlorides have been tested in vitro for their 5-HT_1A and 5-HT_2A receptor affinities. The investigated compounds are potent 5-HT_1A receptor ligands with K_i within range on 5.6-96.5 nM and demonstrate lack of affinity for 5-HT_2A subtype. With respect to the potential multireceptor profile, binding affinity for dopaminergic D₂ receptor was evaluated. The most potent ligands were tested in vivo to evaluate their functional CNS activity.

This study is supported by Polish Ministry of Scientific Research and Information Technology, grant No 2P 05F04226.

1. Lopez-Rodriguez, M. L.; Ayala, D.; Benhamu, B.; Morcillo, M. J.; Viso, A. Curr. Med. Chem. 2002, 9, 443-469.

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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