Synthesis and biological activity of tricyclic aryloimidazo-, pyrimido-, and diazepinopurinediones Original Research Article

Syntheses and physicochemical properties of N-aryl-substituted imidazo-, pyrimido-, and 1,3-diazepino[2,1-f]purinediones are described. These derivatives were synthesized by the cyclization of 7-haloalkyl-8-bromo-1,3-dimethyl- or 1,3-dipropyl-xanthine derivatives with corresponding arylamines. The obtained compounds (1–40), which can be envisaged as sterically fixed and configurationally stable analogs of 8-styrylxanthines, were evaluated for their affinity to adenosine A1 and A2A receptors, the receptor subtypes that are predominant in the brain. Selected compounds were additionally investigated for affinity to the A2B and A3 receptor subtypes. Many of the compounds showed adenosine A2A receptor affinity at micromolar or submicromolar concentrations and were A2A-selective, for example, compound 23 with p-fluoro substituent displayed Ki value of 0.147 μM at the rat A2A receptor and more than 170-fold-A2A selectivity, compound 17 with naphthyl substituent had Ki value of 0.219 μM and a more than 114-fold-A2A selectivity. The compounds were somewhat weaker and less selective at the human receptor subtypes. Elongation of the dimethyl substituent to dipropyl in xanthine moiety improved affinity but reduced selectivity. 1,3-Dimethylimidazo-, pyrimido-, and diazepinopurinediones were evaluated in vivo as anticonvulsants in MES, ScMet, TTE tests and examined for neurotoxicity in mice (ip). Substances with pyrimido ring displayed protective activity in ScMet or in MES and ScMet tests, showing also neurotoxicity. The pyrimidine annelated ring is beneficial for both receptor affinity and anticonvulsant activity.