Novel Inhibitors of Nucleoside Triphosphate Diphosphohydrolases: Chemical Synthesis and Biochemical and Pharmacological Characterizations
journal contributionposted on 11.05.2000, 00:00 by Fernand-Pierre Gendron, Efrat Halbfinger, Bilha Fischer, Martine Duval, Pédro D'Orléans-Juste, Adrien R. Beaudoin
To elucidate the physiological role played by nucleoside triphosphate diphosphohydrolase (NTPDase; EC 220.127.116.11), 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.
Read the peer-reviewed publication
10 μ MP 2X effectPharmacological Characterizationsnucleoside triphosphate diphosphohydrolasepurinergic receptorsNTPDase inhibitorsNTPDase inhibitorNovel InhibitorsP 2Y 1ECATP analoguesnonhydrolyzable analogueK iturkey erythrocytesenzyme sourceguinea pigpurine ringblood pressure variationsprecontracted vessel