Harnessing the Power of the A1 Adenosine Receptor Toward the Development of Cardioprotective Pharmaceuticals

The Peter Scammells group has previously reported the identification of VCP746, a rationally designed adenosine receptor bivalent ligand that has a bitopic mechanism of action and biased profile at the A1 Adenosine Receptor. This compound is a bitopic ligand which consists of the orthosteric agonist adenosine and a biased allosteric thiophene pharmacophore, which are tethered together by an aromatic linker unit and a 6-carbon alkyl linker. Pharmacological evaluation revealed significant bias away from calcium mobilization, compared to ERK1/2 phosphorylation, Akt phosphorylation and inhibition of cAMP accumulation, relative to the reference agonist NECA. Furthermore, this compound was found to have the ability to protect against ischemia in native A1AR-expressing cardiomyoblasts without effects on the rat atrial heart rate. Our proof of concept studies have shown a link between the biased pharmacological profile of VCP746 to its ability to promote on-target efficacy without on-target side effects. This current project aims to further understand the structure-activity relationships of VCP746 and to maximize biased agonism.