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The adenosine A

The adenosine A1 receptor (A1AR) is a potential novel therapeutic target for myocardial ischemia-reperfusion injury. However, to date, clinical translation of prototypical A1AR agonists has been hindered due to dose limiting adverse effects. Recently, we demonstrated that the biased bitopic agonist 1, consisting of an adenosine pharmacophore linked to an allosteric moiety, could stimulate cardioprotective A1AR signaling in the absence of unwanted bradycardia. Therefore, this study aimed to investigate the structure–activity relationship of compound 1 biased agonism. A series of novel derivatives of 1 were synthesized and pharmacologically profiled. Modifications were made to the orthosteric adenosine pharmacophore, linker, and allosteric 2-amino-3-benzoylthiophene pharmacophore to probe the structure–activity relationships, particularly in terms of biased signaling, as well as A1AR activity and subtype selectivity. Collectively, our findings demonstrate that the allosteric moiety, particularly the 4-(trif...

The A1 adenosine receptor (A1AR) is an important G protein-coupled receptor that regulates a range of physiological functions. Herein we report the discovery of novel irreversible agonists acting at the A1AR, which have the potential to serve as useful research tools for studying receptor structure and function. A series of novel adenosine derivatives bearing electrophilic substituents was synthesized, and four compounds, 8b, 15a, 15b, and 15d, were shown to possess similar potency and efficacy to the reference high efficacy agonist, NECA, in an assay of ERK1/2 phosphorylation assay. Insensitivity to antagonist addition in a real-time, label-free, xCELLigence assay was subsequently used to identify compounds that likely mediated their agonism through an irreversible interaction with the A1AR. Of these compounds, 15b and 15d were more directly validated as irreversible agonists of the A1AR using membrane-based [3H]DPCPX and [35S]GTPγS binding experiments.

The A

A series of adenosine-5'-N-alkylcarboxamides and N(6)-(2,2-diphenylethyl)adenosine-5'-N-alkylcarboxamides bearing antioxidant moieties in the 2-position were synthesized from the versatile intermediate, O(6)-(benzotriazol-1-yl)-2-fluoro-2',3'-O-isopropylideneinosine-5'-N-alkylcarboxamide (1). These compounds were evaluated as A(2A) adenosine receptor (A(2A)R) agonists in a cAMP accumulation assay, and a number of potent and selective agonists were identified. Three of these compounds were evaluated further in an ischemic injury cell survival assay and a reactive oxygen species (ROS) production assay whereby 15b and 15c were shown to reduce ROS activity and cell death due to ischemia.