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 naturally 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 ryanodine-sensitive Ca2+-release channels, working independently of inositol 1,4,5-trisphosphate (IP3) to mobilize intracellular Ca2+ stores, In some systems, cADPR has been shown to be more potent than IP3. The chemo-enzymatic synthesis of structurally modified analogues of cADPR can provide pharmacological tools for probing this new Ca2+-signaling pathway. In this work, we describe the synthesis and evaluation of a structural mimic of cADPR with different Ca2+-releasing properties. Results: 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 homogenates made from sea urchin eggs was investigated, 7-Deaza cADPR was more effective in releasing Ca2+ than cADPR, but it only released approximately 66% of the Ca2+ released by a maximal concentration of cADPR, It was also more resistant to hydrolysis than cADPR. If we administered increasing concentrations of 7-deaza cADPR at the same time as a maximal concentration of cADPR, the induction of Ca2+ release by cADPR was antagonized. Conclusions: 7-Deaza cADPR has a Ca2+-release profile consistent with that of a partial agonist, and it is the first reported example of such a compound to act at the cADPR receptor. The imidazole ring of cADPR is clearly important ir stimulating the Ca2+-release machinery, and the present results demonstrate that structural modification of a site other than position 8 of the purine ring can affect the efficacy of Ca2+ release, 7-Deaza cADPR represents a significant step forwards in designing modulators of the cADPR signaling pathway.