1. Discovery and Structure-Activity Relationship Studies of Novel Adenosine A1 Receptor-Selective Agonists
- Author
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Preti, Barbara, Suchankova, Anna, Deganutti, Giuseppe, Leuenberger, Michele, Barkan, Kerry, Manulak, Iga, Huang, Xianglin, Carvalho, Sabrina, Ladds, Graham, Lochner, Martin, Deganutti, Giuseppe [0000-0001-8780-2986], Leuenberger, Michele [0000-0003-0641-4338], Ladds, Graham [0000-0001-7320-9612], Lochner, Martin [0000-0003-4930-1886], and Apollo - University of Cambridge Repository
- Subjects
Adenosine ,Receptors, Purinergic P1 ,610 Medicine & health ,Adenosine-5'-(N-ethylcarboxamide) ,Rats ,Structure-Activity Relationship ,Halogens ,Drug Discovery ,540 Chemistry ,Purinergic P1 Receptor Agonists ,Animals ,Humans ,Molecular Medicine ,570 Life sciences ,biology - Abstract
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.
- Published
- 2022
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