A series of C2-substituted ATP analogues was previously shown to have potent insulin-secreting properties, yet with poor tissue-selectivity for the pancreatic β-cell. The present study was designed to evaluate the binding profile on β-cell membranes and the effects on insulin release and pancreatic vascular resistance of a second generation of P2Y₁ receptor agonists, based on C2-substitution of the adenosine 5′-O-(1-boranotriphosphate) scaffold.

Functional experiments were performed in the rat isolated pancreas model; binding studies with ATP-α-[³⁵S] were performed in membrane homogenates from the rat insulinoma INS-1 cell line. The diastereoisomers of the compounds are designated by A and B.

Under 8.3 mmol l⁻¹ glucose, 2-methylthio-ATP-α-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-α-B, A isomer, was clearly glucose-dependent. This drug competes with ATP-α-[³⁵S] binding in a complex two sites interaction model, with a K _0.5 value of 17.7 nmol l⁻¹. 2-Chloro-ATP-α-B had a similar insulin-secreting profile as 2-methylthio-ATP-α-B, with a lower tissue-selectivity. The non-substituted ATP-α-B analog, A isomer, was less potent than the C2-substituted derivatives (A isomers) and had a vasorelaxant effect.

We conclude that 2-methylthio-ATP-α-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.