J Med Chem 2008 Mar 27;516:1623-36. doi: 10.1021/jm7010386.

2''-deoxy cyclic adenosine 5''-diphosphate ribose derivatives: importance of the 2''-hydroxyl motif for the antagonistic activity of 8-substituted cADPR derivatives.

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The structural features needed for antagonism at the cyclic ADP-ribose (cADPR) receptor are unclear. Chemoenzymatic syntheses of novel 8-substituted 2''-deoxy-cADPR analogues, including 8-bromo-2''-deoxy-cADPR 7, 8-amino-2''-deoxy-cADPR 8, 8- O-methyl-2''-deoxy-cADPR 9, 8-phenyl-2''-deoxy-cADPR 10 and its ribose counterpart 8-phenyl-cADPR 5 are reported, including improved syntheses of established antagonists 8-amino-cADPR 2 and 8-bromo-cADPR 3. Aplysia californica ADP-ribosyl cyclase tolerates even the bulky 8-phenyl-nicotinamide adenine 5''-dinucleotide as a substrate. Structure-activity relationships of 8-substituted cADPR analogues in both Jurkat T-lymphocytes and sea urchin egg homogenate (SUH) were investigated. 2''-OH Deletion decreased antagonistic activity (at least for the 8-amino series), showing it to be an important motif. Some 8-substituted 2''-deoxy analogues showed agonist activity at higher concentrations, among which 8-bromo-2''-deoxy-cADPR 7 was, unexpectedly, a weak but almost full agonist in SUH and was membrane-permeant in whole eggs. Classical antagonists 2 and 3 also showed previously unobserved agonist activity at higher concentrations in both systems. The 2''-OH group, without effect on the Ca (2+)-mobilizing ability of cADPR itself, is an important motif for the antagonistic activities of 8-substituted cADPR analogues.

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Genes referenced: LOC100887844 rbpj