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

Abstract

The concepts of allosteric modulation and biased agonism are revolutionizing modern approaches to drug discovery, particularly in the field of G protein-coupled receptors (GPCRs). Both phenomena exploit topographically distinct binding sites to promote unique GPCR conformations that can lead to different patterns of cellular responsiveness. The adenosine A 1 GPCR (A 1 AR) is a major therapeutic target for cardioprotection, but current agents acting on the receptor are clinically limited for this indication because of ontarget bradycardia as a serious adverse effect. In the current study, we have rationally designed a novel A 1 AR ligand (VCP746)-a hybrid molecule comprising adenosine linked to a positive allosteric modulator-specifically to engender biased signaling at the A 1 AR. We validate that the interaction of VCP746 with the A 1 AR is consistent with a bitopic mode of receptor engagement (i.e., concomitant association with orthosteric and allosteric sites) and that the compound displays biased agonism relative to prototypical A 1 AR ligands. Importantly, we also show that the unique pharmacology of VCP746 is (patho)physiologically relevant, because the compound protects against ischemic insult in native A 1 AR-expressing cardiomyoblasts and cardiomyocytes but does not affect rat atrial heart rate. Thus, this study provides proof of concept that bitopic ligands can be designed as biased agonists to promote on-target efficacy without on-target side effects.

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.…”

Advances in G Protein-Coupled Receptor Allostery: From Function to Structure

“…exploitation of "bitopic" or "dualsteric" ligands, namely, hybrid bifunctional molecules that are composed of two pharmacophores, each known to independently interact with an orthosteric and allosteric site (Disingrini et al, 2006;Steinfeld et al, 2007;Valant et al, 2008Valant et al, , 2009Valant et al, , 2012cValant et al, , 2014Antony et al, 2009;Mohr et al, 2010Mohr et al, , 2013Narlawar et al, 2010;Bock et al, 2012;Lane et al, 2013). Some examples of rationally designed bitopic ligands are shown in Fig.…”

“…This form of selectivity is also particularly pertinent to situations where pure allosteric modulators may lose effectiveness, such as in the context of neurodegenerative disease where endogenous tone is progressively lost while the receptor target remains functional. Another major advantage of bitopic ligands is the potential to engender biased agonism (Antony et al, 2009;Kebig et al, 2009;Valant et al, 2014) because concomitant binding to two different sites may promote unique receptor conformations. A recent successful example of this approach is shown in Fig.…”

Biased Agonism of Endogenous Opioid Peptides at theμ-Opioid Receptor

“…It is now accepted that chemically distinct ligands binding to the same G protein-coupled receptor (GPCR) can stabilize the receptor in multiple active conformations, which results in differential activation of cell signaling pathways and, eventually, in different physiologic outcomes, a phenomenon known as biased agonism (Kenakin et al, 2012). Biased agonism can be exploited to design drugs that selectively activate signaling pathways, leading to the desired physiologic effects while minimizing on-target side effects elicited by activation of other signaling pathways via the same receptor subtype (Gesty-Palmer et al, 2009;Walters et al, 2009;Valant et al, 2014).…”