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
| Autor: | Andrew M. Riley, Megan L. Shipton, Charles A. Brearley, Colin W. Taylor, Barry V. L. Potter, Ana M. Rossi |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Agonist
medicine.drug_class Stereochemistry Cyclitol Inositol 1 4 5-Trisphosphate 01 natural sciences Partial agonist Article Protein Structure Secondary 03 medical and health sciences chemistry.chemical_compound Polyphosphates Drug Discovery medicine Animals Humans Inositol 1 4 5-Trisphosphate Receptors Rats Wistar Receptor 030304 developmental biology 0303 health sciences Dose-Response Relationship Drug Molecular Mimicry Antagonist Regioselectivity Rats 0104 chemical sciences Drug Partial Agonism Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Glucose HEK293 Cells chemistry L-Glucose Molecular Medicine Intracellular |
| Zdroj: | Journal of Medicinal Chemistry |
| Popis: | Chiral sugar derivatives are potential cyclitol surrogates of the Ca2+-mobilizing intracellular messenger d-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3]. Six novel polyphosphorylated analogues derived from both d- and l-glucose were synthesized. Binding to Ins(1,4,5)P3 receptors [Ins(1,4,5)P3R] and the ability to release Ca2+ from intracellular stores via type 1 Ins(1,4,5)P3Rs were investigated. β-d-Glucopyranosyl 1,3,4-tris-phosphate, with similar phosphate regiochemistry and stereochemistry to Ins(1,4,5)P3, and α-d-glucopyranosyl 1,3,4-tris-phosphate are full agonists, being equipotent and 23-fold less potent than Ins(1,4,5)P3, respectively, in Ca2+-release assays and similar to Ins(1,4,5)P3 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)P3R 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)P3R yet identified, providing new leads for antagonist development. |
| Databáze: | OpenAIRE |
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