title: Identification of hydrolytically stable and selective P2Y(1) receptor agonists.
abstract: P2Y nucleotide receptors (P2YRs) are attractive pharmaceutical targets. Most P2YR agonists proposed as drugs consist of a nucleotide scaffold, but their use is limited due to their chemical and enzymatic instabilities. To identify drug candidates, we developed non-hydrolyzable P2YR agonists. We synthesized ATP-beta,gamma-CH(2) analogues 2-4, and evaluated their chemical and metabolic stabilities and activities at P2Y(1,2,4,6) receptors. Analogues 2-4 exhibited t(1/2) values of 14.5-65 h in gastric juice pH. They were completely resistant to alkaline phosphatase for 30 min at 37 degrees C and slowly hydrolyzed in human blood serum (t(1/2) 12.7-71.9 h). In comparison to ATP, analogues 2-4 were barely hydrolyzed by nucleoside triphosphate diphosphohydrolases, NTPDase1,2,3,8 (< 8% hydrolysis), and nucleotide pyrophosphatases, NPP1,3 (< or = 10% hydrolysis). Analogues 2 and 4B were selective agonists of the P2Y(1)R with EC(50)s of 0.08 and 17.2 microM, respectively. These features make analogues 2 and 4B potential therapeutic agents for health disorders involving the P2Y(1)R.
authors.affiliation: Department of Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel.
authors.forename: Shay E
authors.initials: SE
authors.lastname: Eliahu
authors.forename: Jean
authors.initials: J
authors.lastname: Camden
authors.forename: Joanna
authors.initials: J
authors.lastname: Lecka
authors.forename: Gary A
authors.initials: GA
authors.lastname: Weisman
authors.forename: Jean
authors.initials: J
authors.lastname: Sévigny
authors.forename: Sylvie
authors.initials: S
authors.lastname: Gélinas
authors.forename: Bilha
authors.initials: B
authors.lastname: Fischer