A Novel Insulin Secretagogue Based on a Dinucleoside Polyphosphate Scaffold

Abstract

Dinucleoside polyphosphates exert their physiological effects via P2 receptors (P2Rs). They are attractive drug candidates, as they offer better stability and specificity compared to nucleotides, the most common P2 receptor ligands. The activation of pancreatic P2Y receptors by nucleotides increases insulin secretion. Therefore, in the current study, dinucleoside polyphosphate analogues (di-(2-MeS)-adenosine-5′,5″-P1,P4,α,β-methylene-tetraphosphate), 8, (di-(2-MeS)-adenosine-5′,5″-P1,P4,β,γ-methylene-tetraphosphate), 9, and di-(2-MeS)-adenosine-5′,5″-P1,P3,α,β-methylene triphosphate, 10, were developed as potential insulin secretagogues. Analogues 8 and 9 were found to be agonists of the P2Y1R with EC50 values of 0.42 and 0.46 μM, respectively, whereas analogue 10 had no activity. Analogues 8–10 were found to be completely resistant to hydrolysis by alkaline phosphatase over 3 h at 37°C. Analogue 8 also was found to be 2.5-fold more stable in human blood serum than ATP, with a half-life of 12.1 h. Analogue 8 administration in rats caused a decrease in a blood glucose load from 155 mg/dL to ca. 100 mg/dL and increased blood insulin levels 4-fold as compared to basal levels. In addition, analogue 8 reduced a blood glucose load to normal values (80–110 mg/dL), unlike the commonly prescribed glibenclamide, which reduced glucose levels below normal values (60 mg/dL). These findings suggest that analogue 8 may prove to be an effective and safe treatment for type 2 diabetes.

Activation of the P2Y1 receptor induces apoptosis and inhibits proliferation of prostate cancer cells

“…P2 agonists have already been suggested as having a beneficial effect in models of melanoma, in which the P2Y 1 receptor is highly expressed [10]. Other potential therapeutic applications under consideration for P2Y 1 receptor ligands include: selective agonists as antidiabetic agents [32] or selective antagonists as antithrombotic agents [33]. P2Y 1 agonists that are dinucleotides with enhanced in vivo stability have been reported [32].…”

Identification of Highly Promising Antioxidants/Neuroprotectants Based on Nucleoside 5′-Phosphorothioate Scaffold. Synthesis, Activity, and Mechanisms of Action

“…Blood serum contains such enzymes and, therefore, provides a good model system for estimation of the in vivo stability of nucleotide analogues. 42,43 Here, we evaluated the stability of the most promising analogue identified here, 7A, in human blood serum as compared to 2, and 6A.…”

Purinergic signalling in the pancreas in health and disease

“…It has been suggested that 2-methylthio ATP-a-b, A isomer, a potent and tissue-selective P2Y 1 receptor agonist with high efficacy for glucose-dependent insulin secretion, may be a drug candidate for type 2 diabetes (Farret et al 2006). Dinucleoside polyphosphate analogues, which offer better stability compared to nucleotide, acting through P2Y 1 receptors have been developed as insulin secretagogues and it was suggested that they may prove to be an effective and safe treatment for type 2 diabetes (Eliahu et al 2010).…”