title: Designer small molecules to target calcium signalling.
abstract: Synthetic compounds open up new avenues to interrogate and manipulate intracellular Ca2+ signalling pathways. They may ultimately lead to drug-like analogues to intervene in disease. Recent advances in chemical biology tools available to probe Ca2+ signalling are described, with a particular focus on those synthetic analogues from our group that have enhanced biological understanding or represent a step towards more drug-like molecules. 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'-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'-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 vitro and is effective in vivo against induced heart arrhythmia and autoimmune disease, illustrating the therapeutic potential of targeted small molecules.
authors.affiliation: *Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, U.K.
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Swarbrick
authors.affiliation: *Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, U.K.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Riley
authors.affiliation: *Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, U.K.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Mills
authors.affiliation: *Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, U.K.
authors.forename: Barry V L
authors.initials: BV
authors.lastname: Potter
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000627:therapeutic use; D000246:Adenosine Diphosphate Ribose / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D020013:Calcium Signaling / Q000187:drug effects*; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000235:genetics / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000037:antagonists & inhibitors; D009249:NADP / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000235:genetics; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D013329:Structure-Activity Relationship
chemical_list: D002121:Calcium Channel Blockers; D053496:Inositol 1,4,5-Trisphosphate Receptors; D019837:Ryanodine Receptor Calcium Release Channel; D054852:Small Molecule Libraries; C085029:adenophostin A; D000246:Adenosine Diphosphate Ribose; D009249:NADP; C024376:NAADP; D015544:Inositol 1,4,5-Trisphosphate; D000241:Adenosine; D002118:Calcium