Arylpiperazines with an amide moiety are one of the most frequently investigated classes of 5-HT_1A/5-HT_2A receptor ligands. Although the terminal amide fragment significantly affects binding of 1-arylpiperazine derivatives for serotonin receptors, its role is not clear yet [1]. Structure-activity relationship studies showed that the length of the alkyl chain is great importance for 5-HT_1A/5-HT_2A receptor affinities. As a general trend, maximum affinity for 5-HT receptors is reached with 3-4 methylene units [2].
In our earlier attempt to find new 5-HT_1A/5-HT_2A receptor ligands, series of the imidazo[2,1-f]theophylline derivatives with the arylpiperazinylpropyl substituent at N8 position had been synthesized. These compounds have been tested in vitro for their 5-HT_1A and 5-HT_2A receptor affinities and are potent 5-HT_1A receptor ligands with K_i within the range on 5.6-96.5 nM and demonstrate lack of affinity for 5-HT_2A subtype [3]. In this work the series of the imidazo[2,1-f]theophylline derivatives with arylpiperazinylbutyl substituent at N8 position have been synthesized to study the influence of the length of the spacer between the imidazo[2,1-f]theophylline and the arylpiperazine moiety on serotonin receptors activity.

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. Pharmacological in vivo studies directing to CNS receptor profile of the synthesized compounds are in progress.

1. Mokrosz M. J.; Duszyńska B.; Bojarski A. J.; Mokrosz J. L.: Bioorganic & Medicinal Chemistry, 1995, 3, 533-538.
2. Lopez-Rodriguez, M. L.; Ayala, D.; Benhamu, B.; Morcillo, M. J.; Viso, A. Curr. Med. Chem. 2002, 9, 443-469.
3. Zagórska A., Pawłowski M., Dybała M., Nowak G.: Joint Meeting on Medicinal Chemistry, June 20-23, 2005, Vienna, Austria, poster.

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