Synthesis of inositol phosphate-based competitive antagonists of inositol 1,4,5-trisphosphate receptors

• Published in: Organic & biomolecular chemistry 2016-01, Vol.14 (8), p.254-2514
• Main Authors: Konieczny, Vera, Stefanakis, John. G, Sitsanidis, Efstratios D, Ioannidou, Natalia-Anastasia T, Papadopoulos, Nikolaos V, Fylaktakidou, Konstantina C, Taylor, Colin W, Koumbis, Alexandros E
• Format: Article
• Language: English
• Subjects: Animals; Chickens; Dose-Response Relationship, Drug; Inositol 1,4,5-Trisphosphate Receptors - antagonists & inhibitors; Inositol Phosphates - chemical synthesis; Inositol Phosphates - chemistry; Inositol Phosphates - pharmacology; Models, Molecular; Molecular Structure; Structure-Activity Relationship
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/c5ob02623g

Inositol 1,4,5-trisphosphate receptors (IP 3 Rs) 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 IP 3 Rs has defined structure-activity relationships, but existing antagonists have severe limitations. We combined analyses of Ca 2+ release with equilibrium competition binding to IP 3 R to show that (1,3,4,6)IP 4 is a full agonist of IP 3 R1 with lower affinity than (1,4,5)IP 3 . 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)IP 4 and (1,3,4,5,6)IP 5 that compete with (1,4,5)IP 3 for binding to IP 3 R without evoking Ca 2+ release. These novel analogs are the first inositol phosphate-based competitive antagonists of IP 3 Rs with affinities comparable to that of the only commonly used competitive antagonist, heparin, the utility of which is limited by off-target effects. Potent competitive antagonists of the IP 3 receptors, through which Ca 2+ is released in mammalian cells, are synthesized and characterized.