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

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 A1 and A2A receptors. Selected compounds were additionally investigated for affinity to the human A1, A2A, A2B and A3 receptor subtypes. The results of the radioligand binding assays at adenosine A1 and A2A receptors showed that most of the compounds exhibited adenosine A2A receptor affinity at micromolar or submicromolar concentrations; an annelated pyrimidine ring was beneficial for A2A affinity. The most potent A2A ligands of the present series were compounds 6 (Ki 0.33 μM rat A2A, 0.31 μM human A2A), 8 (Ki 0.98 μM rat A2A, 0.42 μM human A2A) and 15 (Ki 0.24 μM rat A2A, 0.61 μM human A2A) with the latter one showing high A2A selectivity. In NaCl shift assay, 15 was shown to be an antagonist at A2A 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 (q2 = 0.88) for A2A 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 A2A antagonists with good water-solubility.

Graphical abstractSyntheses and physicochemical properties of N-cycloalkyl-substituted imidazo-, pyrimido- and 1,3-diazepino[2,1-f]purinediones are described. Most compounds exhibited adenosine A2A receptor (A2A 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 A2A AR affinity was obtained.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Novel cycloalkylimidazo-, pyrimido- and diazepinopurinediones (1–33) were obtained. ► Adenosine A1, A2A R affinities were evaluated in binding studies on rat brain tissues. ► Selected compounds were tested for their affinity to human A1, A2A, A2B and A3 R. ► Anticonvulsant activity (MES, scMet) was evaluated. ► QSAR analysis was performed.