P2Y receptor mediated modulation of insulin release by a novel generation of 2-substituted-5′-O-(1-boranotriphosphate)-adenosine analogues

被引:18
作者
Farret, Anne [1 ]
Filhol, Romain [1 ]
Linck, Nathalie [1 ]
Manteghetti, Michele [1 ]
Vignon, Jacques [1 ]
Gross, Rene [1 ]
Petit, Pierre [1 ]
机构
[1] CNRS, Ctr Pharmacol & Biotechnol Sante, UMR 5160, Fac Pharm, F-34093 Montpellier 5, France
关键词
diabetes; insulin secretion; P2; receptor; P2Y receptor ligand;
D O I
10.1007/s11095-006-9112-4
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Purpose: A series of C2-substituted ATP analogues was previously shown to have potent insulin-secreting properties, yet with poor tissue-selectivity for the pancreatic beta-cell. The present study was designed to evaluate the binding profile on beta-cell membranes and the effects on insulin release and pancreatic vascular resistance of a second generation of P2Y(1) receptor agonists, based on C2-substitution of the adenosine 5'-O-(1-boranotriphosphate) scaffold. Materials and Methods: Functional experiments were performed in the rat isolated pancreas model; binding studies with ATP-alpha-[S-35] were performed in membrane homogenates from the rat insulinoma INS-1 cell line. The diastereoisomers of the compounds are designated by A and B. Results: Under 8.3 mmol l(-1) glucose, 2-methylthio-ATP-alpha-B, A isomer, induced a biphasic and concentration dependent insulin response; its maximal efficacy reaches ninefold the baseline secretion and its EC50 is 28.1 nmol l(-1). No significant effect of this isomer was observed on vascular resistance, whereas the B isomer, which was a less potent insulin secretagogue, consistently induced a transient vasoconstriction. Interestingly, the insulin response induced by 2-methylthio-ATP-alpha-B, A isomer, was clearly glucose-dependent. This drug competes with ATP-alpha-[S-35] binding in a complex two sites interaction model, with a K-0.5 value of 17.7 nmol l(-1). 2-Chloro-ATP-alpha-B had a similar insulin-secreting profile as 2-methylthio-ATP-alpha-B, with a lower tissue-selectivity. The non-substituted ATP-alpha-B analog, A isomer, was less potent than the C2-substituted derivatives (A isomers) and had a vasorelaxant effect. Conclusions: We conclude that 2-methylthio-ATP-alpha-B, A isomer, is a potent and tissue-selective P2Y receptor agonist with high efficacy. Its insulin-releasing action is glucose-dependent, which gives interest to this compound as a drug candidate for treating type 2 diabetes.
引用
收藏
页码:2665 / 2671
页数:7
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