COMPARATIVE EFFECTS OF ADENOSINE-5'-TRIPHOSPHATE AND RELATED ANALOGS ON INSULIN-SECRETION FROM THE RAT PANCREAS

Adenosine tri- and diphosphate (ATP and ADP) and their structural anal ogues stimulate insulin secretion from the isolated perfused rat pancr eas, an effect mediated by P-2Y-purinoceptor activation. Concerning th e base moiety of the nucleotide, it was previously shown that purine b ut not pyrimidine nucleoside triphosphates were active and that substi tution on purine C2 with the 2-methylthio group greatly enhanced the p otency. Tn this study, we further analyze the consequences of ribose a nd polyphosphate chain modifications. Modifications in 2' and 3' posit ion on the ribose led to a decrease in insulin response when bulky sub stitutions were made: indeed, 2'-deoxy ATP was similar in activity to ATP, whereas arylazido-aminopropionyl ATP (ANAPP(3)) was weakly effect ive and trinitrophenyl ATP (TNP-ATP) was inactive. Substitution on the gamma phosphorus of the triphosphate chain led to a decrease (gamma-a nilide ATP) or no change (gamma-azido ATP) in potency; the replacement of the bridging oxygen between beta and gamma phosphorus by a peroxid e group did not significantly change the activity, whereas substitutio n by a methylene group completely abolished stimulation of insulin sec retion. As for the phosphorothioate analogues, adenosine-5'-O-(3-thiot riphosphate) (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 c onclusion, two structural features seem to have a strategic importance for increasing the insulin secretory activity of ATP analogues: subst itution at the C2 position on the adenine ring of ATP and modification s of the polyphosphate chain at the level of the beta phosphorus.