New 8-aminoalkyl derivatives of purine-2,6-dione with arylalkyl,allyl or propynyl substituents in position 7, their 5-HT1A, 5-HT2A,and 5-HT7 receptor affinity and pharmacological evaluation

BackgroundOur previous studies in a group of arylpiperazine derivatives of 1,3-dimethyl-3,7-dihydro-purine-2,6-diones, aimed at chemical diversification of the purine-2,6-dione by introduction of hydrophobic substituent in a 7- or 8- position or elongation of the linker length between arylpiperazine and purine core, allowed a selection of potent 5-HT_1A, 5-HT_2A and 5-HT₇ receptor ligands displaying anxiolytic and antidepressant properties. Continuing our research in this field, in the present studies we designed a new series of 8-aminoalkylamino (15–35) and 8-arylpiperazinylpropoxy (36–42) derivatives of 7-substituted 1,3-dimethyl-3,7-dihydropurine- 2,6-dione as potential 5-HT_1A, 5-HT_2A and 5-HT₇ receptor ligands with potential psychotropic activity.MethodsRadioligand binding assays were employed for determining the affinity and the selectivity profile of the synthesized compounds for native 5-HT_1A, 5-HT_2A, and cloned 5-HT₆ and 5-HT₇ receptors. The functional activity of the selected compounds at 5-HT_1A and 5-HT_2A receptors was tested in the commonly used in vivo models. Antidepressant and anxiolytic properties were evaluated in the forced swim (FST) and the four-plate test (FPT) in mice, respectively.ResultsAmong the evaluated series, selected 7-benzyl-8-((4-(4-(3-chlorophenyl)piperazin-1-yl)butyl)amino)-1,3-dimethyl- 1H-purine-2,6(3H,7H)-dione (21), a mixed 5-HT_1A/5-HT_2A/5-HT₇ receptor ligand, produced an antidepressant-like effect in FST, and exerted anxiolytic-like activity in FPT. Another pharmacologically evaluated compound 42 (a mixed 5-HT_1A/5-HT₇ ligand) slightly, but non-significantly attenuated the immobility time of mice in FST and was devoid of activity in FPT.ConclusionsStudy revealed advantage of mixed 5-HT_1A/5-HT_2A/5-HT₇ receptor ligands over 5-HT_1A/5-HT₇ agents to display antidepressant- and anxiolytic-like activity. Modification of arylalkyl/allyl substituent in position 7 of purine-2,6-dione opens possibility for designing new 5-HT ligands with preserved π electron system and lower molecular weight.