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

Abstract

Inositol 1,4,5-trisphosphate receptors (IP₃Rs) are intracellular Ca²⁺ channels that are widely expressed in animal cells, where they mediate the release of Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ 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.