An analysis of the virtual combinatorial library was used for refining a pilot set of 34 derivatives and designing a targeted 38-member library of the arylamide and arylsulfonamide derivatives of aryloxyethyl- and arylthioethyl- piperidines and pyrrolidines. All compounds were synthesized according to an elaborated parallel solid-phase method and were biologically evaluated for their affinity for 5-HT₇. Additionally, the targeted library members were tested for 5-HT_1A, 5-HT₆, and D₂ receptors.

Selected compounds of particular interest were examined for their intrinsic activity at 5-HT₇R in vitro employing a cAMP assay. The study allowed us to identify compound 68 (4-fluoro-N-(1-{2-[(propan-2-yl)phenoxy]ethyl}piperidin-4-yl) benzenesulfonamide) as a potent 5-HT₇R ligand (K_i = 0.3 nM) with strong antagonistic properties (K_b = 1 nM) and a 1450-fold selectivity over 5-HT_1ARs.

This study was partly supported by the Polish Ministry of Science and Higher Education (MNiSW), Grant No. N N405 671540 and Funds for Statutory Activity of Jagiellonian University Medical College. Radioligand binding experiments were financially supported by the Norwegian Financial Mechanism as part of the Polish-Norwegian Research Fund, Grant No. PNRF–103–AI-1/07.

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