Inhibitory Effect of Novel Pyrimidines on ATP and ADP Hydrolysis in Synaptosomes from Rat Cerebral Cortex

In this study, a new series of trihalomethyl-substituted pyrimidines and dihydropyrimidines were synthesized and tested as potential NTPDase inhibitors. For this purpose, synaptosomes from rat cerebral cortex were used as the enzyme source and ATP and ADP were used as the substrate. Among the new compounds, 4-methyl-2-methylsulfanyl-6-trichloromethylpyrimidine (2b) was found to be the most effective noncompetitive inhibitor, with an estimated K(i) value of 0.18 and 0.55 mM for ATP and ADP, respectively. Other pyrimidines inhibited NTPDase activity with the following rank order of inhibitory potency: 3,6-dimethyl-2-methylsulfanyl-4-trifluoromethyl-3,4-dihydro-pyrimidin-4-ol (3a) > 5-methyl-2-(4-methyl-6-trifluoromethyl-pyrimidin-2-yl)-3-trifluoromethyl-3,4-dihydro-2H-3-pyrazol-3-ol (6a) > 5-bromo-4,6-dimethoxy-4-trichloromethyl-1,2,3,4-tetrahydro-2-pyrimidin-2-one (9) for ATP and 6a > 9 > 3a for ADP. Our results demonstrate that a novel group of pyrimidines compounds can act as inhibitors of ATP and ADP hydrolysis in synaptosomes from rat cerebral cortex. These results can contribute for the understanding of the NTPDase activity and for further studies involving new compounds that can enlist as it inhibitors.