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P006 Designer small molecules to target calcium signalling Joanna M. Swarbrick, Andrew M. Riley, Stephen J. Mills and Barry V.L. Potter University of Bath, Bath, UK Three nucleotide second messengers cADPR, NAADP and ADPR are formed from NAD+ by the multifunctional cyclase CD38. They mobilize Ca2+ using pathways unrelated to myo-inositol1,4,5-trisphosphate (IP3). Synthetic compounds addressing these messengers open new avenues for exploring and manipulating intracellular Ca2+-signalling and may lead to drug-like tools to intervene in disease. Adenophostin is the most potent agonist at the IP3-receptor (IP3R). Our analogues provide a binding model for further design and development. Benzene polyphosphates illustrate that a simple non-inositol template can be engineered to give both IP3R agonists and antagonists. cADPR activates Ca2+ release via the ryanodine receptor. Using a chemoenzymatic or total synthetic route cADPR can be selectively modified, giving chemically and biologically stable tools to investigate structureactivity relationships (SAR), interfere with cADPR synthesis and degradation and agonize/antagonize Ca2+ release. Analogues with a synthetic pyrophosphate bioisostere inhibit cADPR hydrolysis by CD38 and, surprisingly, retain the ability to release Ca2+, suggesting a route to neutral and membrane-permeant tools. Interestingly, preliminary results suggest smaller fragments also exhibit weak activity. ADPR activates TRPM2 a Ca2+, Na+ and K+ permeable cation channel. Synthetic ADPR analogues provide the first SAR for this emerging messenger, and a functional antagonist. An analogue based on the NAADP nicotinic acid motif antagonizes NAADP-mediated Ca2+ release and is effective in vivo in heart arrhythmia and autoimmune disease, illustrating the therapeutic potential of such small molecules.