7-Deaza cyclic adenosine 5'-diphosphate ribose: first example of a Ca(2+)-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 Ca(2+)-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 Ca(2+)-signaling pathway. In this work, we describe the synthesis and evaluation of a structural mimic of cADPR with different Ca(2+)-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 Ca(2+)-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 Ca(2+)-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.
Bailey
V C
VC
Department of Medicinal Chemistry, School of Pharmacy and Pharmacology, University of Bath, UK.
Sethi
J K
JK
Fortt
S M
SM
Galione
A
A
Potter
B V
BV
D000246:Adenosine Diphosphate Ribose / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D036563:Cyclic ADP-Ribose / Q000031:analogs & derivatives; D019204:GTP-Binding Proteins / Q000378:metabolism; D007202:Indicators and Reagents; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008954:Models, Biological; D015394:Molecular Structure; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D012617:Sea Urchins; D015290:Second Messenger Systems; D013329:Structure-Activity Relationship; D014316:Tritium
C106088:7-deaza cyclic adenosine 5'-diphosphate ribose; D007202:Indicators and Reagents; D019269:Phosphatidylinositol 4,5-Diphosphate; D014316:Tritium; D036563:Cyclic ADP-Ribose; D000246:Adenosine Diphosphate Ribose; D015544:Inositol 1,4,5-Trisphosphate; D019204:GTP-Binding Proteins; D002118:Calcium