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
Chiral sugar derivatives are potential cyclitol surrogates in 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] a...
| Main Authors: | , , , |
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| Format: | Journal article |
| Language: | English |
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American Chemical Society
2020
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| _version_ | 1826283293868294144 |
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| author | Brearley, CA Rossi, AM Rossi, AM Brearley, CA Taylor, CW Potter, BVL |
| author_facet | Brearley, CA Rossi, AM Rossi, AM Brearley, CA Taylor, CW Potter, BVL |
| author_sort | Brearley, CA |
| collection | OXFORD |
| description | Chiral sugar derivatives are potential cyclitol surrogates in 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 abilities to release Ca2+ from intracellular stores via type 1 Ins(1,4,5)P3Rs were investigated. β-D-Glucopyranosyl 1,3,4-trisphosphate, with similar phosphate regiochemistry and stereo-chemistry to Ins(1,4,5)P3 and α-D-glucopyranosyl 1,3,4-trisphosphate 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 structure-activity relationship understanding 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 amongst the least efficacious agonists of Ins(1,4,5)P3R yet identified, providing new leads for antagonist development. |
| first_indexed | 2024-03-07T00:56:45Z |
| format | Journal article |
| id | oxford-uuid:88570582-513e-40d2-9fd7-b1ac5e1a1bd1 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T00:56:45Z |
| publishDate | 2020 |
| publisher | American Chemical Society |
| record_format | dspace |
| spelling | oxford-uuid:88570582-513e-40d2-9fd7-b1ac5e1a1bd12022-03-26T22:16:34ZBoth 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 receptorJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:88570582-513e-40d2-9fd7-b1ac5e1a1bd1EnglishSymplectic ElementsAmerican Chemical Society2020Brearley, CARossi, AMRossi, AMBrearley, CATaylor, CWPotter, BVLChiral sugar derivatives are potential cyclitol surrogates in 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 abilities to release Ca2+ from intracellular stores via type 1 Ins(1,4,5)P3Rs were investigated. β-D-Glucopyranosyl 1,3,4-trisphosphate, with similar phosphate regiochemistry and stereo-chemistry to Ins(1,4,5)P3 and α-D-glucopyranosyl 1,3,4-trisphosphate 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 structure-activity relationship understanding 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 amongst the least efficacious agonists of Ins(1,4,5)P3R yet identified, providing new leads for antagonist development. |
| spellingShingle | Brearley, CA Rossi, AM Rossi, AM Brearley, CA Taylor, CW Potter, BVL 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 |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
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