Structure-activity relationships and molecular studies of novel arylpiperazinylalkyl purine-2- 4-diones and purine-2- 4- 8-triones with antidepressant and anxiolytic-like

Authors
Zagórska A, Ko?aczkowski M, Bucki A, Siwek A, Kazek G, Sata?a G, Bojarski AJ, Partyka A, Weso?owska A6, Paw?owski M.

Lab
Department of Medicinal Chemistry, Jagiellonian University Medical College, Kraków, Poland

Journal
Eur J Med Chem.

Abstract
A novel series of arylpiperazinylalkyl purine-2,4-diones (4-27) and purine-2,4,8-triones (31-38) was synthesized and tested to evaluated their affinity for the serotoninergic (5-HT1A, 5-HT6, 5-HT7) and dopaminergic (D2) receptors. Compounds with purine-2,4-dione nucleus generally had affinity values higher than the corresponding purine-2,4,8-trione compounds. A spectrum of receptor activities was observed for compounds with a substituent at the 7-position of the imidazo[2,1-f]purine-2,4-dione system and some potent 5-HT1A (18, 25), 5-HT7 (14) and mixed 5-HT1A/5-HT7 (8, 9) receptor ligands with additional affinity for dopamine D2 receptors (15) has been identified. Moreover, docking studies proved that a substituent at the 7-position of 1,3-dimethyl-(1H,8H)-imidazo[2,1-f]purine-2,4-dione could be essential for receptor affinity and selectivity, especially towards 5-HT1A and 5-HT7. The results of the preliminary pharmacological in vivo studies of selected derivatives of 1,3-dimethyl-(1H,8H)-imidazo[2,1-f]purine-2,4-dione, including 9 as a potential anxiolytic, 8 and 15 as potential antidepressants, and 18 and 25 as potential antidepressant and anxiolytic agents.

BIOSEB Instruments Used:
Aron Test or Four Plates Test (LE830)