| Abstract
| - Cyclic ADP-carbocyclic-ribose (cADPcR, 2) is a biologically and chemically stable equivalent ofcyclic ADP-ribose (cADPR, 1), a Ca2+-mobilizing second messenger. In this study, a series of8-substituted analogues of cADPcR, namely the 8-chloro analogue 6 (8-Cl-cADPcR), the 8-azidoanalogue 7 (8-N3-cADPcR), the 8-amino analogue 8 (8-NH2-cADPcR), and the 8-phenylthioanalogue 9 (8-SPh-cADPcR), were designed as effective pharmacological tools for studies oncADPR-modulated Ca2+ signaling pathways. These target compounds were synthesized by aconvergent route via 8-Cl-cADPcR bisacetonide (14) as the common intermediate, in which amethod for forming the intramolecular pyrophosphate linkage by activation of the phenylthiophosphate type substrate 15 with AgNO3 to produce 14 was used as the key step. The carbocyclicanalogues were tested for activity in the sea urchin egg homogenate system. Compounds wereassessed for their calcium-mobilizing effects and their ability to cross-desensitize with calciumrelease induced by a normally maximal concentration of cADPR, as well as cADPR antagonismof cADPR-evoked calcium release. While cADPcR was 3−4 times more potent than cADPR,the 8-substituted analogues were less efficacious, with 8-SPh-cADPcR largely acting as acompetitive antagonist. Most surprisingly, given that 8-N3-cADPR and 8-NH2-cADPR are knownas potent antagonists, 8-N3-cADPcR and 8-NH2-cADPcR were full agonists, but ca. 80 and 2times less potent than cADPR, respectively. These data contribute to developing structure−activity relationships for the interaction of cADPR with its receptor.
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