Cyclic adenosine diphosphate ribose (cADPR) is a second messenger that when formed in response to extracellular signal causes release of calcium from intracellular stores. Despite decades of study and its role in regulating numerous cellular processes of pharmacological significance, the mechanism of action of cADPR remains poorly understood. Previously we had studied by variable-temperature 1H NMR spectroscopy the detailed conformational behavior of cADPR and several of its analogs. That studied was limited due to the lability of the R-ring N-glycosidic bond in cADPR. The (biologically active) cIDPR analogs below show enhanced stability and allowed for a more detailed 1H NMR investigation; we also found the R-ring conformation to differ from that of cADPR. The dimethoxy cADPR analog was prepared to address an unresolved point in the issue of whether the 2'- and 3'-hydroxyl groups are necessary for activity. Finally, the synthesis and NMR characterization of a potential photoaffinity label to be used for receptor identification studies will be presented.

Tools to probe the SAR in cADPR: conformational analysis of cAPDR and cIDPR analogs and a potential photoaffinity label

256th National Meeting (2018)

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