7-DEAZA CYCLIC ADENOSINE 5'-DIPHOSPHATE RIBOSE - FIRST EXAMPLE OF A CA2-MOBILIZING PARTIAL AGONIST RELATED TO CYCLIC ADENOSINE 5'-DIPHOSPHATE RIBOSE()

Background: Cyclic adenosine 5'-diphosphate ribose (cADPR), a naturall y occurring metabolite of nicotinamide adenine dinucleotide (NAD(+)), mobilizes Ca2+ from non-mitochondrial stores in a variety of mammalian and invertebrate tissues. It has been shown that cADPR activates ryan odine-sensitive Ca2+-release channels, working independently of inosit ol 1,4,5-trisphosphate (IP3) to mobilize intracellular Ca2+ stores, In some systems, cADPR has been shown to be more potent than IP3. The ch emo-enzymatic synthesis of structurally modified analogues of cADPR ca n provide pharmacological tools for probing this new Ca2+-signaling pa thway. In this work, we describe the synthesis and evaluation of a str uctural mimic of cADPR with different Ca2+-releasing properties. Resul ts: 7-Deaza cyclic adenosine 5'-diphosphate ribose (7-deaza cADPR), a novel cADPR analogue modified in the purine ring, was synthesized and its ability to release Ca2+ from non-mitochondrial pools in homogenate s made from sea urchin eggs was investigated, 7-Deaza cADPR was more e ffective in releasing Ca2+ than cADPR, but it only released approximat ely 66% of the Ca2+ released by a maximal concentration of cADPR, It w as also more resistant to hydrolysis than cADPR. If we administered in creasing concentrations of 7-deaza cADPR at the same time as a maximal concentration of cADPR, the induction of Ca2+ release by cADPR was an tagonized. Conclusions: 7-Deaza cADPR has a Ca2+-release profile consi stent with that of a partial agonist, and it is the first reported exa mple of such a compound to act at the cADPR receptor. The imidazole ri ng of cADPR is clearly important ir stimulating the Ca2+-release machi nery, and the present results demonstrate that structural modification of a site other than position 8 of the purine ring can affect the eff icacy of Ca2+ release, 7-Deaza cADPR represents a significant step for wards in designing modulators of the cADPR signaling pathway.