Diinosine polyphosphates, a group of dinucleotides with antagonistic effects on diadenosine polyphosphate receptor

A new family of dinucleotide derivatives, diinosine polyphosphates, has been synthesized through the use of the enzyme 5' adenylic acid deaminase from Aspergillus sp., starting from the corresponding diadenosine polyphosphates. Functional studies were performed on rat brain synaptic terminals in which a dinucleotide receptor has been described that is specific for adenine dinucleotides. The results demonstrated that diinosine polyphosphates did not behave as agonists on the diadenosine polyphosphate receptor (also know as P4 purinoceptor), but they were very efficient as antagonists in abolishing the Ca2+ responses elicited by diadenosine pentaphosphate. The IC50 values for diinosine triphosphate, diinosine tetraphosphate, and diinosine pentaphosphate were 4.90 +/- 0.10 microM, 8.33 +/- 0.22 microM, and 4.23 +/- 0.12 nM, respectively. The diinosine polyphosphates also antagonized the ATP receptors present in synaptic terminals, showing IC50 values of 100.08 +/- 5.72 microM for diinosine triphosphate, 29.51 +/- 1.40 microM for diinosine tetraphosphate and 27.75 +/- 1.65 microM for diinosine pentaphosphate. The antagonistic ability of these diinosine nucleotides was studied in comparison with other P1 and P2 purinoceptor antagonists, such as suramin, pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid, and 8-cyclopentyl-1,3-dipropylxanthine. These purinergic antagonists did not inhibit the response of the P4 purinoceptor; only the diinosine polyphosphates were able to act as antagonists on the dinucleotide receptor. Suramin and pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid attenuated the responses elicited by ATP, as did the diinosine polyphosphate compounds. The most antagonistic diinosine polyphosphate for the dinucleotide and ATP receptors was diinosine pentaphosphate, which was 6000 times more selective for the P4 purinoceptor than it was for the ATP receptor.