Quantification of adenosine A 1 receptor biased agonism: Implications for drug discovery

Structure-Activity Analysis of Biased Agonism at the Human Adenosine A3 Receptor

“…A 1 AR-biased agonism has been previously investigated (Langemeijer et al, 2013;Valant et al, 2014;Baltos et al, 2016) and recently demonstrated to allow for the selective stimulation of cardioprotective signal transduction in the absence of the adverse hemodynamic effects commonly associated with A 1 AR therapies (Valant et al, 2014). The current study has identified a range of bias profiles for subtype selective A 3 AR agonists, which offer a potential therapeutic advantage.…”

New paradigms in adenosine receptor pharmacology: allostery, oligomerization and biased agonism

“…At the molecular level, biased agonism is thought to arise due to the stabilization of different active receptor conformations, leading to the engagement of an alternative subset of intracellular effectors, and in turn, the activation of differential signalling pathways (Figure ). Much of the early work on GPCR bias examined G protein‐dependent versus G protein‐independent β‐arrestin signalling (Kenakin and Christopoulos, ); however, it is also recognized that ligand bias can be detected within G protein‐dependent pathways (Baltos et al, ).…”

“…The recognition that observed bias is influenced by cellular context also gives rise to the idea of context‐dependent bias, whereby, conceivably, the receptor bias can change with alterations in membrane composition and intracellular signalling complement, for example, as a consequence of disease progression. However, the generation of bias fingerprints does provide the opportunity to screen and identify compounds that display a distinct profile from the endogenous ligand and are therefore more likely to engender different pharmacological outcomes, presenting a promising starting point with which to move lead compounds into more physiologically relevant in vitro and in vivo models (Baltos et al, ).…”

“…This study suggested that biased agonism at the A 1 receptor was most likely to be a rare phenomenon. However, A 1 receptor‐biased agonism has recently been shown to arise from differences within G protein‐dependent pathways, potentially due to differential coupling to the various G i/o proteins in particular (Valant et al, ; Baltos et al, ). A 1 receptor‐biased agonism was identified using the rationally designed bitopic agonist VCP746, which was shown to be significantly biased away from Ca 2+ mobilization compared to other G protein‐dependent pathways.…”

“…A 1 receptor‐biased agonism was identified using the rationally designed bitopic agonist VCP746, which was shown to be significantly biased away from Ca 2+ mobilization compared to other G protein‐dependent pathways. The ability of VCP746 to stimulate A 1 receptor‐biased agonism, relative to the reference agonist, was postulated to underlie its novel cytoprotective actions in the heart in the absence of typical A 1 receptor‐mediated bradycardia (Valant et al, ; Baltos et al, ). Similarly, capadenoson, an adenosine receptor agonist that has previously entered clinical trials for angina and atrial fibrillation (Bayer, ; Tendera et al, ), was also shown to be an A 1 receptor‐biased agonist within G protein‐dependent pathways (Baltos et al, ).…”