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


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.

SUBMITTER: Preti B 

PROVIDER: S-EPMC9661479 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Discovery and Structure-Activity Relationship Studies of Novel Adenosine A<sub>1</sub> Receptor-Selective Agonists.

Preti Barbara B   Suchankova Anna A   Deganutti Giuseppe G   Leuenberger Michele M   Barkan Kerry K   Manulak Iga I   Huang Xianglin X   Carvalho Sabrina S   Ladds Graham G   Lochner Martin M  

Journal of medicinal chemistry 20221021 21


A series of benzyloxy and phenoxy derivatives of the adenosine receptor agonists <i>N</i><sup>6</sup>-cyclopentyl adenosine (CPA) and <i>N</i><sup>6</sup>-cyclopentyl 5'-<i>N</i>-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 <i>meta</i> position on the aromatic ring of the benzyloxy- or phenoxycyclopentyl substituent. In general, the NECA-based compounds displayed gr  ...[more]

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