Cargando…
Synthesis of Terminal Ribose Analogues of Adenosine 5′-Diphosphate Ribose as Probes for the Transient Receptor Potential Cation Channel TRPM2
[Image: see text] TRPM2 (transient receptor potential cation channel, subfamily M, member 2) is a nonselective cation channel involved in the response to oxidative stress and in inflammation. Its role in autoimmune and neurodegenerative diseases makes it an attractive pharmacological target. Binding...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2019
|
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6528165/ https://www.ncbi.nlm.nih.gov/pubmed/30978018 http://dx.doi.org/10.1021/acs.joc.9b00338 |
_version_ | 1783420158272864256 |
---|---|
author | Baszczyňski, Ondřej Watt, Joanna M. Rozewitz, Monika D. Guse, Andreas H. Fliegert, Ralf Potter, Barry V. L. |
author_facet | Baszczyňski, Ondřej Watt, Joanna M. Rozewitz, Monika D. Guse, Andreas H. Fliegert, Ralf Potter, Barry V. L. |
author_sort | Baszczyňski, Ondřej |
collection | PubMed |
description | [Image: see text] TRPM2 (transient receptor potential cation channel, subfamily M, member 2) is a nonselective cation channel involved in the response to oxidative stress and in inflammation. Its role in autoimmune and neurodegenerative diseases makes it an attractive pharmacological target. Binding of the nucleotide adenosine 5′-diphosphate ribose (ADPR) to the cytosolic NUDT9 homology (NUDT9H) domain activates the channel. A detailed understanding of how ADPR interacts with the TRPM2 ligand binding domain is lacking, hampering the rational design of modulators, but the terminal ribose of ADPR is known to be essential for activation. To study its role in more detail, we designed synthetic routes to novel analogues of ADPR and 2′-deoxy-ADPR that were modified only by removal of a single hydroxyl group from the terminal ribose. The ADPR analogues were obtained by coupling nucleoside phosphorimidazolides to deoxysugar phosphates. The corresponding C2″-based analogues proved to be unstable. The C1″- and C3″-ADPR analogues were evaluated electrophysiologically by patch-clamp in TRPM2-expressing HEK293 cells. In addition, a compound with all hydroxyl groups of the terminal ribose blocked as its 1″-β-O-methyl-2″,3″-O-isopropylidene derivative was evaluated. Removal of either C1″ or C3″ hydroxyl groups from ADPR resulted in loss of agonist activity. Both these modifications and blocking all three hydroxyl groups resulted in TRPM2 antagonists. Our results demonstrate the critical role of these hydroxyl groups in channel activation. |
format | Online Article Text |
id | pubmed-6528165 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-65281652019-05-22 Synthesis of Terminal Ribose Analogues of Adenosine 5′-Diphosphate Ribose as Probes for the Transient Receptor Potential Cation Channel TRPM2 Baszczyňski, Ondřej Watt, Joanna M. Rozewitz, Monika D. Guse, Andreas H. Fliegert, Ralf Potter, Barry V. L. J Org Chem [Image: see text] TRPM2 (transient receptor potential cation channel, subfamily M, member 2) is a nonselective cation channel involved in the response to oxidative stress and in inflammation. Its role in autoimmune and neurodegenerative diseases makes it an attractive pharmacological target. Binding of the nucleotide adenosine 5′-diphosphate ribose (ADPR) to the cytosolic NUDT9 homology (NUDT9H) domain activates the channel. A detailed understanding of how ADPR interacts with the TRPM2 ligand binding domain is lacking, hampering the rational design of modulators, but the terminal ribose of ADPR is known to be essential for activation. To study its role in more detail, we designed synthetic routes to novel analogues of ADPR and 2′-deoxy-ADPR that were modified only by removal of a single hydroxyl group from the terminal ribose. The ADPR analogues were obtained by coupling nucleoside phosphorimidazolides to deoxysugar phosphates. The corresponding C2″-based analogues proved to be unstable. The C1″- and C3″-ADPR analogues were evaluated electrophysiologically by patch-clamp in TRPM2-expressing HEK293 cells. In addition, a compound with all hydroxyl groups of the terminal ribose blocked as its 1″-β-O-methyl-2″,3″-O-isopropylidene derivative was evaluated. Removal of either C1″ or C3″ hydroxyl groups from ADPR resulted in loss of agonist activity. Both these modifications and blocking all three hydroxyl groups resulted in TRPM2 antagonists. Our results demonstrate the critical role of these hydroxyl groups in channel activation. American Chemical Society 2019-04-12 2019-05-17 /pmc/articles/PMC6528165/ /pubmed/30978018 http://dx.doi.org/10.1021/acs.joc.9b00338 Text en Copyright © 2019 American Chemical Society This is an open access article published under a Creative Commons Attribution (CC-BY) License (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) , which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited. |
spellingShingle | Baszczyňski, Ondřej Watt, Joanna M. Rozewitz, Monika D. Guse, Andreas H. Fliegert, Ralf Potter, Barry V. L. Synthesis of Terminal Ribose Analogues of Adenosine 5′-Diphosphate Ribose as Probes for the Transient Receptor Potential Cation Channel TRPM2 |
title | Synthesis of Terminal
Ribose Analogues of Adenosine
5′-Diphosphate Ribose as Probes for the Transient Receptor
Potential Cation Channel TRPM2 |
title_full | Synthesis of Terminal
Ribose Analogues of Adenosine
5′-Diphosphate Ribose as Probes for the Transient Receptor
Potential Cation Channel TRPM2 |
title_fullStr | Synthesis of Terminal
Ribose Analogues of Adenosine
5′-Diphosphate Ribose as Probes for the Transient Receptor
Potential Cation Channel TRPM2 |
title_full_unstemmed | Synthesis of Terminal
Ribose Analogues of Adenosine
5′-Diphosphate Ribose as Probes for the Transient Receptor
Potential Cation Channel TRPM2 |
title_short | Synthesis of Terminal
Ribose Analogues of Adenosine
5′-Diphosphate Ribose as Probes for the Transient Receptor
Potential Cation Channel TRPM2 |
title_sort | synthesis of terminal
ribose analogues of adenosine
5′-diphosphate ribose as probes for the transient receptor
potential cation channel trpm2 |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6528165/ https://www.ncbi.nlm.nih.gov/pubmed/30978018 http://dx.doi.org/10.1021/acs.joc.9b00338 |
work_keys_str_mv | AT baszczynskiondrej synthesisofterminalriboseanaloguesofadenosine5diphosphateriboseasprobesforthetransientreceptorpotentialcationchanneltrpm2 AT wattjoannam synthesisofterminalriboseanaloguesofadenosine5diphosphateriboseasprobesforthetransientreceptorpotentialcationchanneltrpm2 AT rozewitzmonikad synthesisofterminalriboseanaloguesofadenosine5diphosphateriboseasprobesforthetransientreceptorpotentialcationchanneltrpm2 AT guseandreash synthesisofterminalriboseanaloguesofadenosine5diphosphateriboseasprobesforthetransientreceptorpotentialcationchanneltrpm2 AT fliegertralf synthesisofterminalriboseanaloguesofadenosine5diphosphateriboseasprobesforthetransientreceptorpotentialcationchanneltrpm2 AT potterbarryvl synthesisofterminalriboseanaloguesofadenosine5diphosphateriboseasprobesforthetransientreceptorpotentialcationchanneltrpm2 |