Both d- and l-Glucose Polyphosphates Mimic d-myo-Inositol 1,4,5-Trisphosphate: New Synthetic Agonists and Partial Agonists at the Ins(1,4,5)P₃ Receptor

Abstract

Chiral sugar derivatives are potential cyclitol surrogates of the Ca 2+ -mobilizing intracellular messenger D-myoinositol 1,4,5-trisphosphate [Ins(1,4,5)P 3 ]. Six novel polyphosphorylated analogues derived from both D-and L-glucose were synthesized. Binding to Ins(1,4,5)P 3 receptors [Ins(1,4,5)P 3 R] and the ability to release Ca 2+ from intracellular stores via type 1 Ins(1,4,5)P 3 Rs were investigated. β-D-Glucopyranosyl 1,3,4-trisphosphate, with similar phosphate regiochemistry and stereochemistry to Ins(1,4,5)P 3 , and α-D-glucopyranosyl 1,3,4-trisphosphate are full agonists, being equipotent and 23-fold less potent than Ins(1,4,5)P 3 , respectively, in Ca 2+ -release assays and similar to Ins(1,4,5)P 3 and 15-fold weaker in binding assays. They can be viewed as truncated analogues of adenophostin A and refine understanding of structure-activity relationships for this Ins(1,4,5)P 3 R agonist. L-Glucose-derived ligands, methyl α-Lglucopyranoside 2,3,6-trisphosphate and methyl α-L-glucopyranoside 2,4,6-trisphosphate, are also active, while their corresponding D-enantiomers, methyl α-D-glucopyranoside 2,3,6-trisphosphate and methyl α-D-glucopyranoside 2,4,6-trisphosphate, are inactive. Interestingly, both L-glucose-derived ligands are partial agonists: they are among the least efficacious agonists of Ins(1,4,5)P 3 R yet identified, providing new leads for antagonist development.

Substrate promiscuity of inositol 1,4,5-trisphosphate kinase driven by structurally-modified ligands and active site plasticity

“…All final target compounds studied were used as their triethylammonium salts and were of >95% purity as judged by HPLC methodology as described 58 . Briefly, compounds were detected by post-column complexation with ferric ion after anion-exchange separation on a CarboPac PA200 (Dionex) column eluted with methane sulfonic acid 59 .…”

“…The following other ligands investigated were synthesized as described, purified by ion exchange chromatography, quantified using a Briggs phosphate assay and used as their triethylammonium salts; they were >95% pure by NMR spectroscopy: l - scyllo -inositol 1,2,4-trisphosphate 1-s 60 , d - myo -inositol 1,4,6-trisphosphate 2-s 34 , d -3-deoxy- myo -inositol 1,4,6-trisphosphate 3-s 36 , l - chiro -inositol 2,3,5-trisphosphate 4-s 35 , β- d -glucopyranosyl 1,3,4-trisphosphate 6a-s 59 , α- d -glucopyranosyl 1,3,4-trisphosphate 6b–s 59 , β- d -glucopyranosylmethanol 3,4,1’-trisphosphate 7a–s , α- d -glucopyranosylmethanol 3,4,1’-trisphosphate 7b–s 44 , 45 , ribophostin 8 and d - chiro -inositol ribophostin 9 28 .…”

Inositol 1,4,5-trisphosphate receptors in cardiomyocyte physiology and disease

“…While this mercury based agent may sensitise InsP 3 Rs, it has multiple other targets including induction of Zn release from cellular stores [145]. The issues raised above highlight the need for future development and application of improved InsP 3 R probes such as those involving modified versions of InsP 3 [146] or of the carbon ring on which it is based [147]. These new tools should be used together with advanced imaging approaches to selectively interrogate the localization and function of InsP 3 Rs.…”

Inositol Adenophostin: Convergent Synthesis of a Potent Agonist of d-myo-Inositol 1,4,5-Trisphosphate Receptors

“…25 Most recently, polyphosphorylated analogues derived from both D-and L-glucose were synthesized, some of which can be viewed as truncated analogues of AdA that refine SAR understanding. 26 Removal of the adenine moiety or an electron-rich aromatic ring from the C1′-position of AdA leads to analogues (Figure 4, compounds 4, 14, 15) with reduced potency. 10,17 Furanophostin (15) and ribophostin (4), in which the adenine is replaced with a H or methoxyl group, respectively, have similar potency to IP 3 , revealing the minimal substitution at C1′ to achieve potent receptor activation.…”

“…Acyclophostin has a slightly higher affinity than IP 3 , but its Ca 2+ -mobilizing activity is pH-dependent . Most recently, polyphosphorylated analogues derived from both d - and l -glucose were synthesized, some of which can be viewed as truncated analogues of AdA that refine SAR understanding …”