title: Inhibitory effect of novel pyrimidines on ATP and ADP hydrolysis in synaptosomes from rat cerebral cortex.
abstract: 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.
authors: Departamento de Química, Setor de Bioquímica, Centro de Ciências Naturais e Exatas, and Núcleo de Química de Heterociclos (NUQUIMHE), Universidade Federal de Santa Maria, Santa Maria, RS, Brazil, 97105-900.
authors: Sirlene R
authors: SR
authors: Cechin
authors: Maria Rosa C
authors: MR
authors: Schetinger
authors: Nilo
authors: N
authors: Zanatta
authors: Claudia C
authors: CC
authors: Madruga
authors: Iraci L
authors: IL
authors: Pacholski
authors: Darlene C
authors: DC
authors: Flores
authors: Helio G
authors: HG
authors: Bonacorso
authors: Marcos A P
authors: MA
authors: Martins
authors: Vera M
authors: VM
authors: Morsch
mesh_terms: D000244:Adenosine Diphosphate / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001938:Brazil; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D006868:Hydrolysis / Q000187:drug effects; D011720:Pyrazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000493:pharmacokinetics; D051381:Rats; D013574:Synaptosomes / Q000187:drug effects* / Q000201:enzymology
chemical_list: C495782:3,6-dimethyl-2-methylsulfanyl-4-trifluoromethyl-3,4-dihydropyrimidin-4-ol; C495781:4-methyl-2-methylsulfanyl-6-trichloromethylpyrimidine; C495784:5-bromo-4,6-dimethoxy-4-trichloromethyl-1,2,3,4-tetrahydro-2-pyrimidin-2-one; C495783:5-methyl-2-(4-methyl-6-trifluoromethylpyrimidin-2-yl)-3-trifluoromethyl-3,4-dihydro-2H-3-pyrazol-3-ol; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate