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.
Cechin
Sirlene R
SR
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.
Schetinger
Maria Rosa C
MR
Zanatta
Nilo
N
Madruga
Claudia C
CC
Pacholski
Iraci L
IL
Flores
Darlene C
DC
Bonacorso
Helio G
HG
Martins
Marcos A P
MA
Morsch
Vera M
VM
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
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