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Adenophostin (AdA) is the most potent known agonist at the inositol 1,4,5-trisphosphate receptor (IP3R) and synthetic analogues provide a binding model for receptor activation and channel opening. 2-O-Modified inositol 1,4,5-trisphosphate (IP3) derivatives that are partial agonists at the IP3R reveal key conformational changes of the receptor upon ligand binding. Biphenyl polyphosphates illustrate that simple non-inositol surrogates can be engineered to give prototype IP3R agonists or antagonists and act as templates for protein co-crystallization. Cyclic adenosine 5\u2032-diphosphoribose (cADPR) can be selectively modified using total synthesis, generating chemically and biologically stable tools to investigate Ca2+ release via the ryanodine receptor (RyR) and to interfere with cADPR synthesis and degradation. The first neutral analogues with a synthetic pyrophosphate bioisostere surprisingly retain the ability to release Ca2+, suggesting a new route to membrane-permeant tools. Adenosine 5\u2032-diphosphoribose (ADPR) activates the Ca2+-, Na+- and K+-permeable transient receptor potential melastatin 2 (TRPM2) cation channel. Synthetic ADPR analogues provide the first structure-activity relationship (SAR) for this emerging messenger and the first functional antagonists. An analogue based on the nicotinic acid motif of nicotinic acid adenine dinucleotide phosphate (NAADP) antagonizes NAADP-mediated Ca2+ release in\u00a0vitro and is effective in\u00a0vivo against induced heart arrhythmia and autoimmune disease, illustrating the therapeutic potential of targeted small molecules.<\/jats:p>","DOI":"10.1042\/bst20140293","type":"journal-article","created":{"date-parts":[[2015,5,26]],"date-time":"2015-05-26T15:15:34Z","timestamp":1432653334000},"page":"417-425","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Designer small molecules to target calcium signalling"],"prefix":"10.1042","volume":"43","author":[{"given":"Joanna\u00a0M.","family":"Swarbrick","sequence":"first","affiliation":[{"name":"Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew\u00a0M.","family":"Riley","sequence":"additional","affiliation":[{"name":"Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen\u00a0J.","family":"Mills","sequence":"additional","affiliation":[{"name":"Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barry\u00a0V.L.","family":"Potter","sequence":"additional","affiliation":[{"name":"Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, U.K."},{"name":"Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2015,6,1]]},"reference":[{"key":"2021111719380414500_B1","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1038\/35036035","article-title":"The versatility and universality of calcium signalling","volume":"1","author":"Berridge","year":"2000","journal-title":"Nat. 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