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

Background: our 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-ht1a,5-ht2a 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-ht1a,5-ht2a and 5-ht7 receptor ligands with potential psychotropic activity. methods: radioligand binding assays were employed for determining the affinity and the selectivity profile of the synthesized compounds for native 5-ht1a,5-ht2a,and cloned 5-ht6 and 5-ht7 receptors. the functional activity of the selected compounds at 5-ht1a and 5-ht2a 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. results: among 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-ht1a/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-ht1a/5-ht 7 ligand) slightly,but non-significantly attenuated the immobility time of mice in fst and was devoid of activity in fpt. conclusions: study revealed advantage of mixed 5-ht1a/5-ht2a/5-ht7 receptor ligands over 5-ht1a/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 p electron system and lower molecular weight. copyright © 2013 by institute of pharmacology polish academy of sciences.