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Discovery and Structure-Activity Relationship Studies of Novel Adenosine A1 Receptor-Selective Agonists.

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Preti, Barbara 
Suchankova, Anna 
Deganutti, Giuseppe  ORCID logo
Leuenberger, Michele  ORCID logo
Barkan, Kerry 


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.



Animals, Humans, Rats, Adenosine, Adenosine-5'-(N-ethylcarboxamide), Halogens, Purinergic P1 Receptor Agonists, Receptors, Purinergic P1, Structure-Activity Relationship

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J Med Chem

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American Chemical Society (ACS)