Cyclic ADP-ribose analogues containing the methylenebisphosphonate linkage: Effect of pyrophosphate modifications on Ca²⁺ release activity

Analogues of cyclic ADP-ribose (cADPR) incorporating a methylenebisphosphonate linkage in the place of the pyrophosphate have been synthesized from nicotinamide adenine dinucleotide analogues enzymatically using Aplysia californica ADP-ribosyl cyclase. Methylenebisphosphonate cyclic ADP-ribose (CADPR[CH₂]) and methylenebisphosphonate cyclic 3-deaza-ADP-ribose (3-deaza-cADPR[CH₂]) showed full agonist activity for release of Ca²⁺ ions from sea urchin egg homogenates. The EC ₅₀ for cADPR [CH₂] was 856 nM and that for 3-deaza-cADPR [CH₂] was 300 nM, about 15- and 5-fold less potent than cADPR, respectively.