Functional selectivity of adenosine A1 receptor ligands?

Abstract

The concept of functional selectivity offers great potential for the development of drugs that selectively activate a specific intracellular signaling pathway. During the last few years, it has become possible to systematically analyse compound libraries on G protein-coupled receptors (GPCRs) for this 'biased' form of signaling. We screened over 800 compounds targeting the class of adenosine A(1) receptors using a β-arrestin-mediated signaling assay in U2OS cells as a G protein-independent readout for GPCR activation. A selection of compounds was further analysed in a G protein-mediated GTPγS assay. Additionally, receptor affinity of these compounds was determined in a radioligand binding assay with the agonist [(3)H]CCPA. Of all compounds tested, only LUF5589 9 might be considered as functionally selective for the G protein-dependent pathway, particularly in view of a likely overestimation of β-arrestin signaling in the U2OS cells. Altogether, our study shows that functionally selective ligands for the adenosine A(1) receptor are rare, if existing at all. A thorough analysis of biased signaling on other GPCRs also reveals that only very few compounds can be considered functionally selective. This might indicate that the concept of functional selectivity is less common than speculated.

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.…”

Adenosine receptors as drug targets — what are the challenges?

“…The functional selectivity of different signalling pathways offers a new opportunity for developing signalling pathway-biased drugs that selectively activate a specific intracellular adenosine receptor signalling pathway that is essential for a particular biological function. By systematically screening compound libraries of GPCRs for this ‘biased’ form of signalling, β-arrestin-biased D 2 receptor ligands were successfully identified 245 and the discovery of a β-arrestin-biased A 1 receptor ligand was also attempted, albeit with limited success 246 . New knowledge of the diversity and modularity of GPCR structures, the A 2A receptor in particular, from a recent structural biology crystallization study offers opportunities to target receptor structures with different signalling functions 239 .…”

Separation of on-target efficacy from adverse effects through rational design of a bitopic adenosine receptor agonist

“…Our study presents a variation on these methods, in that we purposefully exploit the allosteric nature of GPCRs to maximize the likelihood that a biased ligand can be rationally engineered from the outset. This approach is especially noteworthy given that previous screening studies have been unable to identify biased ligands at the A 1 AR (47,48). Moreover, assaying of the engineered biased ligand in native A 1 AR-expressing systems revealed unique properties, suggesting a favorable efficacy vs. side effect profile.…”