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Cyclic ADP-carbocyclic-ribose (cADPcR, 2) is a biologically and chemically stable equivalent of cyclic ADP-ribose (cADPR, 1), a Ca(2+)-mobilizing second messenger. In this study, a series of 8-substituted analogues of cADPcR, namely the 8-chloro analogue 6 (8-Cl-cADPcR), the 8-azido analogue 7 (8-N(3)-cADPcR), the 8-amino analogue 8 (8-NH(2)-cADPcR), and the 8-phenylthio analogue 9 (8-SPh-cADPcR), were designed as effective pharmacological tools for studies on cADPR-modulated Ca(2+) signaling pathways. These target compounds were synthesized by a convergent route via 8-Cl-cADPcR bisacetonide (14) as the common intermediate, in which a method for forming the intramolecular pyrophosphate linkage by activation of the phenylthiophosphate type substrate 15 with AgNO(3) to produce 14 was used as the key step. The carbocyclic analogues were tested for activity in the sea urchin egg homogenate system. Compounds were assessed for their calcium-mobilizing effects and their ability to cross-desensitize with calcium release induced by a normally maximal concentration of cADPR, as well as cADPR antagonism of 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 a competitive antagonist. Most surprisingly, given that 8-N(3)-cADPR and 8-NH(2)-cADPR are known as potent antagonists, 8-N(3)-cADPcR and 8-NH(2)-cADPcR were full agonists, but ca. 80 and 2 times less potent than cADPR, respectively. These data contribute to developing structure-activity relationships for the interaction of cADPR with its receptor.

Original publication

DOI

10.1021/jm030227f

Type

Journal article

Journal

J Med Chem

Publication Date

23/10/2003

Volume

46

Pages

4741 - 4749

Keywords

Animals, Calcium, Calcium Signaling, Cyclic ADP-Ribose, In Vitro Techniques, Molecular Mimicry, Ovum, Sea Urchins, Structure-Activity Relationship