Preti, Barbara; Suchankova, Anna; Deganutti, Giuseppe; Leuenberger, Michele; Barkan, Kerry; Manulak, Iga; Huang, Xianglin; Carvalho, Sabrina; Ladds, Graham; Lochner, Martin (2022). Discovery and Structure-Activity Relationship Studies of Novel Adenosine A1 Receptor-Selective Agonists. Journal of medicinal chemistry, 65(21), pp. 14864-14890. American Chemical Society 10.1021/acs.jmedchem.2c01414
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A series of benzyloxy and phenoxy derivatives of the adenosine receptor agonists N6-cyclopentyl adenosine (CPA) and N6-cyclopentyl 5'-N-ethylcarboxamidoadenosine (CP-NECA) were synthesized, and their potency and selectivity were assessed. We observed that the most potent were the compounds with a halogen in the meta position on the aromatic ring of the benzyloxy- or phenoxycyclopentyl substituent. In general, the NECA-based compounds displayed greater A1R selectivity than the adenosine-based compounds, with N6-2-(3-bromobenzyloxy)cyclopentyl-NECA and N6-2-(3-methoxyphenoxy)cyclopentyl-NECA showing ∼1500-fold improved A1R selectivity compared to NECA. In addition, we quantified the compounds' affinity and kinetics of binding at both human and rat A1R using a NanoBRET binding assay and found that the halogen substituent in the benzyloxy- or phenoxycyclopentyl moiety seems to confer high affinity for the A1R. Molecular modeling studies suggested a hydrophobic subpocket as contributing to the A1R selectivity displayed. We believe that the identified selective potent A1R agonists are valuable tool compounds for adenosine receptor research.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine |
UniBE Contributor: |
Preti, Barbara, Leuenberger, Michele, Lochner, Martin |
Subjects: |
500 Science > 570 Life sciences; biology 600 Technology > 610 Medicine & health 500 Science > 540 Chemistry |
ISSN: |
0022-2623 |
Publisher: |
American Chemical Society |
Funders: |
[4] Swiss National Science Foundation ; [UNSPECIFIED] Cambridge Trust ; [UNSPECIFIED] Leverhulme Trust ; [UNSPECIFIED] Astra Zeneca Studentship ; [UNSPECIFIED] British Pharmacology Society Vacation Studentship ; [UNSPECIFIED] BBSRC ; [UNSPECIFIED] China Scholarship Council Cambridge International Scholarship |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
25 Oct 2022 16:08 |
Last Modified: |
05 Dec 2022 16:26 |
Publisher DOI: |
10.1021/acs.jmedchem.2c01414 |
PubMed ID: |
36270633 |
BORIS DOI: |
10.48350/173993 |
URI: |
https://boris.unibe.ch/id/eprint/173993 |
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