title: Novel inhibitors of nucleoside triphosphate diphosphohydrolases: chemical synthesis and biochemical and pharmacological characterizations.
abstract: To 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 K(i) of 10 microM. 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 P2Y(1)-receptor-mediated effect, it therefore appears that this NTPDase inhibitor does not interfere with purinergic receptors.
authors.affiliation: Départment de Biologie, Université de Sherbrooke, Canada.
authors.forename: F P
authors.initials: FP
authors.lastname: Gendron
authors.forename: E
authors.initials: E
authors.lastname: Halbfinger
authors.forename: B
authors.initials: B
authors.lastname: Fischer
authors.forename: M
authors.initials: M
authors.lastname: Duval
authors.forename: P
authors.initials: P
authors.lastname: D'Orléans-Juste
authors.forename: A R
authors.initials: AR
authors.lastname: Beaudoin
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001081:Apyrase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002417:Cattle; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D006868:Hydrolysis; D007700:Kinetics; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D058910:Purinergic P2 Receptor Agonists; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2; D000255:Adenosine Triphosphate; D001081:Apyrase