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.
Journal Title: Pharmacological Reports - Year 2013, Vol 65, Issue 1
Abstract
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-HT2A/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-HT7 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.
Authors and Affiliations
Grażyna Chłoń-Rzepa, Paweł Zmudzki, Grzegorz Satała, Beata Duszyńska, Anna Partyka, Dagmara Wróbel, Magdalena Jastrzębska-Więsek, Andrzej J Bojarski, Maciej Pawłowski
Keywords
Related Articles
- EP ID EP103975
- DOI -
- Views 74
- Downloads 0
Possible contribution of IGF-1 to depressive disorder.
Depression is an illness of unknown origin and involves the dysregulation of many physiological processes disturbed in this disease. It has been postulated that the pathomechanism of depression is complex, and apart from...
Biotechnology and genetic engineering in the new drug development. Part I. DNA technology and recombinant proteins.
Pharmaceutical biotechnology has a long tradition and is rooted in the last century, first exemplified by penicillin and streptomycin as low molecular weight biosynthetic compounds. Today, pharmaceutical biotechnology st...
Alpha(1) and alpha(2)-adrenoreceptor antagonists in streptozotocin- and vincristine-induced hyperalgesia.
The effect of alpha(1)- and alpha(2)-adrenoreceptor antagonists (prazosin and yohimbine, respectively) on streptozotocin (STZ)- and vincristine (VIN)-induced hyperalgesia in rats was studied. In two experimental models,...
Cytisine inhibits the anticonvulsant activity of phenytoin and lamotrigine in mice.
Background: Cytisine (CYT), the most commonly used drug for smoking cessation in Poland, was experimentally found to induce convulsions. There is a lack of studies on the influence of CYT on the anticonvulsant activity o...
Lymphocyte-suppressing action of simvastatin in patients with isolated hypertriglyceridemia.
Background: No previous study examined whether statins affect lymphocyte cytokine release in patients with isolated hypertriglyceridemia. Methods: The study included 46 patients with elevated triglyceride levels and peri...