Dinucleoside polyphosphates, NpnN′, exert their physiological effects via P2 receptors (P2Rs). NpnN′ are attractive drug candidates as they offer better stability and specificity compared to nucleotides, the most common P2R ligands. To further improve the agonist properties of NpnN′, we synthesized novel isosters of dinucleoside polyphosphates where N and N′ are A or U and where the Pα or Pβ phosphate groups are replaced by boranophosphate, denoted as Npn(α-B)N′ or Npn(β-B)N′ (n = 3, 4), respectively. The potency of Npn(α/β-B)N′ analogues was evaluated at tP2Y1, hP2Y2, hP2Y4, and rP2Y6 receptors. The most potent P2Y1R and P2Y6R agonists were the Up4(β-B)A (A isomer, EC50 of 0.5 μM vs 0.004 μM for 2-SMe-ADP) and Up3(α-B)U (B isomer, EC50 of 0.3 μM vs 0.2 μM for UDP), respectively. The receptor subtype selectivity is controlled by the position of the borano moiety on the NpnN′ polyphosphate chain and the type of the nucleobase. In addition, Npn(α/β-B)N′ proved ~22-fold more resistant to hydrolysis by e-NPP1, as compared to the corresponding NpnN′ analogues. In summary, Up4(β-B)A and Up3(α-B)U are potent, stable, and highly selective P2Y1 and P2Y6 receptor agonists, respectively.
The activation by ettracellular nucleotides of pancreatic P2Y receptors, particularly, the P2Y1R subtype, increases insulin secretion. Therefure, we developed analogues of the P2Y1R receptor agonist 2 MeS ADP, as potential antidiabetic drugs. Analogue 3A was found to be a potent P2Y1R agonist (EC50 = 0.038 μM vs 0.0025 μM for 2 MeS-ADP) showing no activity at P2Y21416Rs. Analogue 3A was stable at pH 1.4 (t½ = 7.3 h) and resistant to hydrolysis vs 2-MeS ADP by alkaline phosphatase (t½ = 6 vs 4.5 h), human e-NPPl (4% vs 16% hydrolysis after 20 min), and hwnan blood serum (30% vs 50% hydrolysis after 24 h). Intravenous administration of 3A in naive rats decreased blood glucose from 155 mg/dL to normal values, ca. 87 mg/dL, unlike glibenclamide, leading to subnormal values (i.e., 63 mg/dL). Similar observations were made for strepto2otocin (STZ) treated and db+/db− mouse models. Furthermore, 3A inhibits platelet aggregation in vitro and elongates bleeding time in mice (iv administration of 30 mg of 3A/kg), increasing bleeding time to 16 vs 9 min for Prasugrel. Oral administration of30 mg/kg 3A to rats increased tail bleeding volwne, similar to aspirin. These findings suggest that 3A may be an effective treatment for type 2 diabetes by reducing both blood glucose levels and platelet aggregation.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.