ATP analogues and the guinea-pig taenia coli: a comparison of the structure-activity relationships of ectonucleotidases with those of the P2-purinoceptor.

The dephosphorylation of adenine nucleotides and their analogues by ectonucleotidases on the guinea-pig taenia coli was studied using HPLC. The rate of dephosphorylation of each analogue was compared with its pharmacological potency relative to ATP. ATP, ADP and AMP were rapidly dephosphorylated, and substitution on the purine ring had no effect upon the rate of breakdown. The ectonucleotidases showed stereoselectivity towards the ribose, the unnatural L enantiomers of nucleotides being dephosphorylated more slowly. Analogues in which one of the oxygen atoms on the terminal phosphate had been replaced were resistant to degradation. Phosphorothioate analogues in which a sulphur was attached to the penultimate phosphorus were degraded stereoselectively. Methylene isosteres of ATP and ADP resisted degradation, except for homo-ATP which was dephosphorylated at the same rate as ATP. Overall, no correlation was found between the potency of an analogue and its rate of degradation.