title: Synthesis of inositol phosphate-based competitive antagonists of inositol 1,4,5-trisphosphate receptors.
abstract: Inositol 1,4,5-trisphosphate receptors (IP3Rs) are intracellular Ca(2+) channels that are widely expressed in animal cells, where they mediate the release of Ca(2+) from intracellular stores evoked by extracellular stimuli. A diverse array of synthetic agonists of IP3Rs has defined structure-activity relationships, but existing antagonists have severe limitations. We combined analyses of Ca(2+) release with equilibrium competition binding to IP3R to show that (1,3,4,6)IP4 is a full agonist of IP3R1 with lower affinity than (1,4,5)IP3. Systematic manipulation of this meso-compound via a versatile synthetic scheme provided a family of dimeric analogs of 2-O-butyryl-(1,3,4,6)IP4 and (1,3,4,5,6)IP5 that compete with (1,4,5)IP3 for binding to IP3R without evoking Ca(2+) release. These novel analogs are the first inositol phosphate-based competitive antagonists of IP3Rs with affinities comparable to that of the only commonly used competitive antagonist, heparin, the utility of which is limited by off-target effects.
authors.affiliation: Department of Pharmacology, Tennis Court Road, Cambridge, CB2 1PD, UK. cwt1000@cam.ac.uk.
authors.forename: Vera
authors.initials: V
authors.lastname: Konieczny
authors.affiliation: Laboratory of Organic Chemistry, Chemistry Department, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece. akoumbis@chem.auth.gr.
authors.forename: John G
authors.initials: JG
authors.lastname: Stefanakis
authors.affiliation: Laboratory of Organic Chemistry, Chemistry Department, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece. akoumbis@chem.auth.gr.
authors.forename: Efstratios D
authors.initials: ED
authors.lastname: Sitsanidis
authors.affiliation: Laboratory of Organic Chemistry, Chemistry Department, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece. akoumbis@chem.auth.gr.
authors.forename: Natalia-Anastasia T
authors.initials: NA
authors.lastname: Ioannidou
authors.affiliation: Laboratory of Organic Chemistry, Chemistry Department, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece. akoumbis@chem.auth.gr.
authors.forename: Nikolaos V
authors.initials: NV
authors.lastname: Papadopoulos
authors.affiliation: Laboratory of Organic, Bioorganic and Natural Product Chemistry, Molecular Biology and Genetics Department, Democritus University of Thrace, 68100 Alexandroupolis, Greece.
authors.forename: Konstantina C
authors.initials: KC
authors.lastname: Fylaktakidou
authors.affiliation: Department of Pharmacology, Tennis Court Road, Cambridge, CB2 1PD, UK. cwt1000@cam.ac.uk.
authors.forename: Colin W
authors.initials: CW
authors.lastname: Taylor
authors.affiliation: Laboratory of Organic Chemistry, Chemistry Department, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece. akoumbis@chem.auth.gr.
authors.forename: Alexandros E
authors.initials: AE
authors.lastname: Koumbis
mesh_terms: D000818:Animals; D002645:Chickens; D004305:Dose-Response Relationship, Drug; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000037:antagonists & inhibitors*; D007295:Inositol Phosphates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D007295:Inositol Phosphates