The A1 adenosine receptor (A1AR) is a potential novel therapeutic target for myocardial ischemia-reperfusion injury. However, clinical translation of prototypical A1AR agonists has been hindered to date due to dose limiting adverse effects. Recently, we demonstrated that the biased bitopic agonist VCP746 (1), consisting of an adenosine pharmacophore linked to an allosteric moiety, could stimulate cardioprotective A1AR signalling in the absence of unwanted bradycardia. We subsequently investigated the structure-activity relationships associated with this biased agonism. A series of novel derivatives of 1 were synthesised 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 signalling, as well as A1AR activity and subtype selectivity. Collectively, our findings demonstrate that the allosteric moiety, particularly the 4-(trifluoromethyl)phenyl substituent of the thiophene scaffold, is important in conferring bitopic ligand bias at the A1AR.<br/><br/>To further understand the structural basis this compound’s mechanism of action we solved the first X-ray structure of the A1AR, which was stabilized using DU172, an irreversible antagonist developed previously by our group. We have also successfully designed a series of novel irreversible agonists. Four of these compounds were shown to have similar potency and efficacy to the reference agonist, NECA, together with the ability to stabilize purified receptors in a ThermoFluor assay to a significantly higher degree than NECA. Accordingly, these irreversible agonists may prove to be valuable tool molecules in ongoing structural studies.

Bitopic ligands acting at the A<sub>1</sub> adenosine receptor

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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Bitopic ligands acting at the A1 adenosine receptor

Bitopic ligands acting at the A₁ adenosine receptor