Comparative effects of adenosine-5′-triphosphate and related analogues on insulin secretion from the rat pancreas
| Autor: | Marie-Madeleine Loubatières-Mariani, Pierre Petit, G. Bertrand, Dominique Hillaire-Buys, D Pujalte, J. Chapal |
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| Rok vydání: | 1997 |
| Předmět: |
Purine
Azides Ribose medicine.medical_treatment In Vitro Techniques Biology Islets of Langerhans Structure-Activity Relationship chemistry.chemical_compound Adenosine Triphosphate Deoxyadenine Nucleotides Polyphosphates Adenine nucleotide Insulin Secretion medicine Animals Insulin Pharmacology (medical) Nucleotide Pancreas Pharmacology chemistry.chemical_classification Receptors Purinergic P2 Polyphosphate Thionucleotides Adenosine Rats Adenosine Diphosphate chemistry Biochemistry Area Under Curve Nucleoside medicine.drug |
| Zdroj: | Fundamental & Clinical Pharmacology. 11:537-545 |
| ISSN: | 1472-8206 0767-3981 |
| Popis: | Adenosine tri- and diphosphate (ATP and ADP) and their structural analogues stimulate insulin secretion from the isolated perfused rat pancreas, an effect mediated by P2Y-purinoceptor activation. Concerning the base moiety of the nucleotide, it was previously shown that purine but not pyrimidine nucleoside triphosphates were active and that substitution on purine C2 with the 2-methylthio group greatly enhanced the potency. In this study, we further analyze the consequences of ribose and polyphosphate chain modifications. Modifications in 2' and 3' position on the ribose led to a decrease in insulin response when bulky substitutions were made: indeed, 2'-deoxy ATP was similar in activity to ATP, whereas arylazido-aminopropionyl ATP (ANAPP3) was weakly effective and trinitrophenyl ATP (TNP-ATP) was inactive. Substitution on the gamma phosphorus of the triphosphate chain led to a decrease (gamma-anilide ATP) or no change (gamma-azido ATP) in potency; the replacement of the bridging oxygen between beta and gamma phosphorus by a peroxide group did not significantly change the activity, whereas substitution by a methylene group completely abolished stimulation of insulin secretion. As for the phosphorothioate analogues, adenosine-5'-O-(3-thiotriphosphate) (ATP gamma S) induced an insulin response similar to that produced by ATP, whereas adenosine-5'-O-(2-thiodiphosphate) (ADP beta S) was about 100-fold more potent than ATP, as previously shown. In conclusion, two structural features seem to have a strategic importance for increasing the insulin secretory activity of ATP analogues: substitution at the C2 position on the adenine ring of ATP and modifications of the polyphosphate chain at the level of the beta phosphorus. |
| Databáze: | OpenAIRE |
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