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P2Y Receptor Mediated Modulation of Insulin Release by a Novel Generation of 2-Substituted-5′-O-(1-Boranotriphosphate)-Adenosine Analogues

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Abstract

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 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.

Materials and Methods

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.

Results

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.

Conclusions

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.

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Acknowledgment

The authors wish to thank Mr. Michel Tournier for expert technical assistance.

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Authors and Affiliations

  1. Centre de Pharmacologie et Biotechnologie pour la Santé, CNRS UMR 5160, Faculté de Pharmacie, 15 Avenue Charles Flahault, BP 14491, 34093, Montpellier cedex 5, France

    Anne Farret, Romain Filhol, Nathalie Linck, Michèle Manteghetti, Jacques Vignon,  René Gross & Pierre Petit

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  1. Anne Farret
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  2. Romain Filhol
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  3. Nathalie Linck
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  4. Michèle Manteghetti
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  6. René Gross
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  7. Pierre Petit
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Correspondence to Pierre Petit.

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Farret, A., Filhol, R., Linck, N. et al. P2Y Receptor Mediated Modulation of Insulin Release by a Novel Generation of 2-Substituted-5′-O-(1-Boranotriphosphate)-Adenosine Analogues. Pharm Res 23, 2665–2671 (2006). https://doi.org/10.1007/s11095-006-9112-4

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  • DOI: https://doi.org/10.1007/s11095-006-9112-4

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