Anti-inflammatory, antioxidant, and antiparkinsonian effects of adenosine A_2A receptor antagonists

The purpose of the study was to examine derivatives of annelated xanthines (imidazo-, pyrimido-, and diazepino-purinediones) for potential anti-inflammatory effects in carrageenan-induced paw edema in mice. Additionally, their antioxidant activity using the FRAP (ferric-reducing ability of plasma) assay and lipid peroxidation in rat brain homogenate were analyzed. All the studied derivatives showed affinity for adenosine A_2A receptor. The preliminary assays found that five (KD-114, KD-57, KD-129, KD-50, and KD-358) pyrimidopurinedione derivatives, administered intraperitoneally (i.p.) at a dose of 100mg/kg, had stronger anti-inflammatory effects. At a concentration of 10^-5M, three of the derivatives KD-57, KD-114, and KD-129 most influenced the total antioxidant ability. The most efficient anti-inflammatory compound, KD-114, also showed the strongest binding to A_2A receptors and when administered at a dose of 5mg/kg (i.p.), effectively reversed haloperidol-induced catalepsy and significantly increased the striatal extracellular dopamine level in the rat striatum. This effect was weaker than the one produced by CSC (1mg/kg i.p.), and only slightly weaker than that produced by ZM 241385 (3mg/kg i.p.) used as reference drugs. From the results of the present studies, it may be concluded that anti-inflammatory and antiparkinsonian effects of the examined compounds correlate with their influence on adenosine A_2A receptors, the most probable antagonism to these subtype receptors.