Based on our previous systematic studies on the structure-activity relationships in arylalkylpiperazine group of serotonin receptor ligands [1-3] we designed and synthesized a set of new 8-alkoxy-1,3-dimethyl-purine-2,6-dione derivatives with 7-(4-phenyl-1-pipera-zinyl)-alkyl and 7-(4-tetrahydroisoquinolinyl)-alkyl moieties. Previously obtained
1,3-dimethyl-7-(3-chloroalkyl)-8-alkoxy-purine-2,6-diones, in the reaction with appropriate piperazine derivatives and 1,2,3,4-tetrahydroisoquinoline yielded final products, which were then converted into water soluble hydrochloride salts. The purity of the compounds were controlled by TLC, the structures were confirmed by spectral (¹H-NMR, MS, UV), and C, H, N analyses.

The new compounds were tested in competition binding experiments for 5-HT_1A,
5-HT_2A and 5-HT₇ receptors. It was found that some of 7-(4-phenylpiperazinyl)-butyl derivatives were potent 5-HT_1A, and/or 5-HT_2A receptor ligands (K_i = 11-28 nM), and also highly active 5-HT₇ ligands (K_i = 75-90 nM). The compound with 7-(4-tetra-hydroisoquinolinyl)-butyl moiety was selective 5-HT₇ receptor ligand (K_i = 106 nM) with moderate 5-HT_1A, and low 5-HT_2A receptor affinity. Some behavioral models demonstrated that selected compounds may be classified as partial agonists of 5-HT_1A receptor.

References

1. M. Pawłowski, G. Chłoń, J. Obniska, A. Zejc, S. Charakchieva-Minol, M.J. Mokrosz: Il Farmaco, 55, 461, 2000.

2. G. Chłoń, M. Pawłowski, B. Duszyńska, A. Szaro, E. Tatarczyńska, A. Kłodzińska, E. Chojnacka-Wójcik: Pol. J. Pharmacol., 53, 359, 2001.

3. P. Zajdel, A.J. Bojarski, H. Byrtus, G. Chłoń-Rzepa, J. Obniska, P. Chevallet, J. Martinez, M. Pawłowski: Biomed. Chromatogr. 17, 312, 2003.

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