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)P 3 Receptor

Chiral sugar derivatives are potential cyclitol surrogates of the Ca -mobilizing intracellular messenger d- -inositol 1,4,5-trisphosphate [Ins(1,4,5)P ]. Six novel polyphosphorylated analogues derived from both d- and l-glucose were synthesized. Binding to Ins(1,4,5)P receptors [Ins(1,4,5)P R] and t...

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Published in:Journal of medicinal chemistry 2020-05, Vol.63 (10), p.5442-5457
Main Authors: Shipton, Megan L, Riley, Andrew M, Rossi, Ana M, Brearley, Charles A, Taylor, Colin W, Potter, Barry V L
Format: Article
Language:English
Subjects:
Animals
Dose-Response Relationship, Drug
Drug Partial Agonism
Glucose - chemistry
Glucose - pharmacology
HEK293 Cells
Humans
Inositol 1,4,5-Trisphosphate - chemistry
Inositol 1,4,5-Trisphosphate - pharmacology
Inositol 1,4,5-Trisphosphate Receptors - agonists
Inositol 1,4,5-Trisphosphate Receptors - chemistry
Molecular Docking Simulation - methods
Molecular Mimicry - drug effects
Molecular Mimicry - physiology
Polyphosphates - chemistry
Polyphosphates - pharmacology
Protein Structure, Secondary
Rats
Rats, Wistar
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Summary:Chiral sugar derivatives are potential cyclitol surrogates of the Ca -mobilizing intracellular messenger d- -inositol 1,4,5-trisphosphate [Ins(1,4,5)P ]. Six novel polyphosphorylated analogues derived from both d- and l-glucose were synthesized. Binding to Ins(1,4,5)P receptors [Ins(1,4,5)P R] and the ability to release Ca from intracellular stores via type 1 Ins(1,4,5)P Rs were investigated. β-d-Glucopyranosyl 1,3,4-tris-phosphate, with similar phosphate regiochemistry and stereochemistry to Ins(1,4,5)P , and α-d-glucopyranosyl 1,3,4-tris-phosphate are full agonists, being equipotent and 23-fold less potent than Ins(1,4,5)P , respectively, in Ca -release assays and similar to Ins(1,4,5)P 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 R agonist. l-Glucose-derived ligands, methyl α-l-glucopyranoside 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 R yet identified, providing new leads for antagonist development.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.0c00215