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Novel Inhibitors of Nucleoside Triphosphate Diphosphohydrolases: Chemical Synthesis and Biochemical and Pharmacological Characterizations
journal contribution
posted on 2000-05-11, 00:00 authored by Fernand-Pierre Gendron, Efrat Halbfinger, Bilha Fischer, Martine Duval, Pédro D'Orléans-Juste, Adrien R. BeaudoinTo elucidate the physiological role played by nucleoside triphosphate diphosphohydrolase
(NTPDase; EC 3.6.1.5), adenine nucleotide analogues, modified on the purine ring, have been
synthesized and tested as potential inhibitors. Resistance of ATP analogues to hydrolysis and
their potency as NTPDase inhibitors were evaluated. For this purpose, a particulate fraction
isolated from bovine spleen was used as the enzyme source. Among the synthesized analogues,
8-thiobutyladenosine 5‘-triphosphate (8-BuS-ATP) was found to be the most effective nonhydrolyzable competitive inhibitor, with an estimated Ki of 10 μM. This nonhydrolyzable analogue
did not exert any P2X-receptor-mediated effect on endothelium-denuded blood vessels, from
the guinea pig mesenteric bed. In agreement with this observation, infusion of the analogue
did not cause any significant blood pressure variations of the precontracted vessel. Because in
previous studies on isolated turkey erythrocytes and rat astrocytes 8-BuS-ATP was not able
to trigger any P2Y1-receptor-mediated effect, it therefore appears that this NTPDase inhibitor
does not interfere with purinergic receptors.
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10 μ MP 2X effectPharmacological Characterizationsnucleoside triphosphate diphosphohydrolasepurinergic receptorsNTPDase inhibitorsNTPDase inhibitorNovel InhibitorsP 2Y 1ECATP analoguesnonhydrolyzable analogueK iturkey erythrocytesenzyme sourceguinea pigpurine ringblood pressure variationsprecontracted vessel
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