7-Deaza cyclic adenosine 5'-diphosphate ribose: First example of a Ca²⁺-mobilizing partial agonist related to cyclic adenosine 5'-diphosphate ribose

Bailey, Victoria C., Sethi, Jaswinder K., Fortt, Simon M., Galione, Antony and Potter, Barry V.L. (1997) 7-Deaza cyclic adenosine 5'-diphosphate ribose: First example of a Ca²⁺-mobilizing partial agonist related to cyclic adenosine 5'-diphosphate ribose. Chemistry & Biology, 4 (1), 51-61. (doi:10.1016/S1074-5521(97)90236-2).

Abstract

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 in 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.

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Contributors

Author: Jaswinder K. Sethi

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