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

• 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
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c00215

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.