Synthesis and biological activity of tricyclic cycloalkylimidazo-, pyrimido- and diazepinopurinediones

• Published in: European journal of medicinal chemistry 2011-09, Vol.46 (9), p.3590-3607
• Main Authors: Drabczyńska, Anna, Yuzlenko, Olga, Köse, Meryem, Paskaleva, Minka, Schiedel, Anke C., Karolak-Wojciechowska, Janina, Handzlik, Jadwiga, Karcz, Tadeusz, Kuder, Kamil, Müller, Christa E., Kieć-Kononowicz, Katarzyna
• Format: Article
• Language: English
• Subjects: Adenosine A 1 and A 2A receptor antagonists; Animals; Anticonvulsants. Antiepileptics. Antiparkinson agents; Biological and medical sciences; CHO Cells; Cricetinae; Cricetulus; Crystallography, X-Ray; Cyclization; Cycloalkyl-1,3-diazepino[2,1- f]purinediones; Humans; Hydrogen Bonding; Medical sciences; Models, Molecular; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Purines - chemical synthesis; Purines - chemistry; Purines - pharmacology; Quantitative Structure-Activity Relationship; Radioligand Assay; Rats; Receptor, Adenosine A1 - drug effects; Receptor, Adenosine A2A - drug effects; Tricyclic xanthine derivatives
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2011.05.023

Syntheses and physicochemical properties of N-cycloalkyl-substituted imidazo-, pyrimido- and 1,3-diazepino[2,1- f]purinediones are described. These derivatives were synthesized by cyclization of 7-halogenoalkyl-8-bromo-1,3-dimethylxanthine derivatives with aminocycloalkanes. The obtained compounds ( 1– 33) were evaluated for their affinity to rat adenosine A 1 and A 2A receptors. Selected compounds were additionally investigated for affinity to the human A 1, A 2A, A 2B and A 3 receptor subtypes. The results of the radioligand binding assays at adenosine A 1 and A 2A receptors showed that most of the compounds exhibited adenosine A 2A receptor affinity at micromolar or submicromolar concentrations; an annelated pyrimidine ring was beneficial for A 2A affinity. The most potent A 2A ligands of the present series were compounds 6 ( K i 0.33 μM rat A 2A, 0.31 μM human A 2A), 8 ( K i 0.98 μM rat A 2A, 0.42 μM human A 2A) and 15 ( K i 0.24 μM rat A 2A, 0.61 μM human A 2A) with the latter one showing high A 2A selectivity. In NaCl shift assay, 15 was shown to be an antagonist at A 2A receptors. This result was confirmed for the best compounds 6, 8, 15 in cAMP accumulation studies. A 3D-QSAR equation with a good predicting power ( q 2 = 0.88) for A 2A AR affinity was obtained. The compounds were evaluated in vivo as anticonvulsants in MES and ScMet tests and examined for neurotoxicity in mice (i.p.). Most of them showed anticonvulsant activity in chemically induced seizures; among them the diazepinopurinediones were the best (e.g. 31) showing protection in both tests on short time symptoms, without signs of neurotoxicity. Five compounds, 8, 17, 20, 29, and 31, exhibited anticonvulsant activity after peroral application in rats. Structure–activity relationships are discussed including the analysis of lipophilic and spatial properties. The new compounds, which contain a basic nitrogen atom and can therefore be protonated, may be good starting points for obtaining A 2A antagonists with good water-solubility. Syntheses and physicochemical properties of N-cycloalkyl-substituted imidazo-, pyrimido- and 1,3-diazepino[2,1- f]purinediones are described. Most compounds exhibited adenosine A 2A receptor (A 2A AR) affinity at micromolar or submicromolar concentrations and showed anticonvulsant activity in chemically induced seizures without signs of neurotoxicity. A QSAR equation with a good predicting power for A 2A AR affinity was obtained. [Display omitted] ► Novel cycloal