Development of subtype-selective covalent ligands for the adenosine A 2B receptor by tuning the reactive group
Signalling through the adenosine receptors (ARs), in particular through the adenosine A receptor (A AR), has been shown to play a role in a variety of pathological conditions, ranging from immune disorders to cancer. Covalent ligands for the A AR have the potential to irreversibly block the receptor...
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| Veröffentlicht in: | RSC medicinal chemistry 2022-07, Vol.13 (7), p.850-856 |
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| container_start_page | 850 |
| container_title | RSC medicinal chemistry |
| container_volume | 13 |
| creator | Beerkens, Bert L H Wang, Xuesong Avgeropoulou, Maria Adistia, Lisa N van Veldhoven, Jacobus P D Jespers, Willem Liu, Rongfang Heitman, Laura H IJzerman, Adriaan P van der Es, Daan |
| description | Signalling through the adenosine receptors (ARs), in particular through the adenosine A
receptor (A
AR), has been shown to play a role in a variety of pathological conditions, ranging from immune disorders to cancer. Covalent ligands for the A
AR have the potential to irreversibly block the receptor, as well as inhibit all A
AR-induced signalling pathways. This will allow a thorough investigation of the pathophysiological role of the receptor. In this study, we synthesized and evaluated a set of potential covalent ligands for the A
AR. The ligands all contain a core scaffold consisting of a substituted xanthine, varying in type and orientation of electrophilic group (warhead). Here, we find that the right combination of these variables is necessary for a high affinity, irreversible mode of binding and selectivity towards the A
AR. Altogether, this is the case for sulfonyl fluoride 24 (LUF7982), a covalent ligand that allows for novel ways to interrogate the A
AR. |
| doi_str_mv | 10.1039/d2md00132b |
| format | Article |
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receptor (A
AR), has been shown to play a role in a variety of pathological conditions, ranging from immune disorders to cancer. Covalent ligands for the A
AR have the potential to irreversibly block the receptor, as well as inhibit all A
AR-induced signalling pathways. This will allow a thorough investigation of the pathophysiological role of the receptor. In this study, we synthesized and evaluated a set of potential covalent ligands for the A
AR. The ligands all contain a core scaffold consisting of a substituted xanthine, varying in type and orientation of electrophilic group (warhead). Here, we find that the right combination of these variables is necessary for a high affinity, irreversible mode of binding and selectivity towards the A
AR. Altogether, this is the case for sulfonyl fluoride 24 (LUF7982), a covalent ligand that allows for novel ways to interrogate the A
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receptor (A
AR), has been shown to play a role in a variety of pathological conditions, ranging from immune disorders to cancer. Covalent ligands for the A
AR have the potential to irreversibly block the receptor, as well as inhibit all A
AR-induced signalling pathways. This will allow a thorough investigation of the pathophysiological role of the receptor. In this study, we synthesized and evaluated a set of potential covalent ligands for the A
AR. The ligands all contain a core scaffold consisting of a substituted xanthine, varying in type and orientation of electrophilic group (warhead). Here, we find that the right combination of these variables is necessary for a high affinity, irreversible mode of binding and selectivity towards the A
AR. Altogether, this is the case for sulfonyl fluoride 24 (LUF7982), a covalent ligand that allows for novel ways to interrogate the A
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receptor (A
AR), has been shown to play a role in a variety of pathological conditions, ranging from immune disorders to cancer. Covalent ligands for the A
AR have the potential to irreversibly block the receptor, as well as inhibit all A
AR-induced signalling pathways. This will allow a thorough investigation of the pathophysiological role of the receptor. In this study, we synthesized and evaluated a set of potential covalent ligands for the A
AR. The ligands all contain a core scaffold consisting of a substituted xanthine, varying in type and orientation of electrophilic group (warhead). Here, we find that the right combination of these variables is necessary for a high affinity, irreversible mode of binding and selectivity towards the A
AR. Altogether, this is the case for sulfonyl fluoride 24 (LUF7982), a covalent ligand that allows for novel ways to interrogate the A
AR.</abstract><cop>England</cop><pmid>35923720</pmid><doi>10.1039/d2md00132b</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0003-3662-8177</orcidid><orcidid>https://orcid.org/0000-0002-2884-3961</orcidid></addata></record> |
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| ispartof | RSC medicinal chemistry, 2022-07, Vol.13 (7), p.850-856 |
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| language | eng |
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| source | Royal Society Of Chemistry Journals 2008-; PubMed Central |
| title | Development of subtype-selective covalent ligands for the adenosine A 2B receptor by tuning the reactive group |
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