Tactical Approaches to Interconverting GPCR Agonists and Antagonists

Abstract

There are many reported examples of small structural modifications to GPCR-targeted ligands leading to major changes in their functional activity, converting agonists into antagonists or vice versa. These shifts in functional activity are often accompanied by negligible changes in binding affinity. The current perspective focuses on outlining and analyzing various approaches that have been used to interconvert GPCR agonists, partial agonists, and antagonists in order to achieve the intended functional activity at a GPCR of therapeutic interest. An improved understanding of specific structural modifications that are likely to alter the functional activity of a GPCR ligand may be of use to researchers designing GPCR-targeted drugs and/or probe compounds, specifically in cases where a particular ligand exhibits good potency but not the preferred functional activity at the GPCR of choice.

Quantitative Structural Assessment of Graded Receptor Agonism

“…This would not be a trivial task as it would require knowledge of ligand binding poses and a precise understanding of how small chemical modifications affect ligand affinity and stabilization of functional surfacestwo distinct but important consequences of ligand-receptor interactions. In structure-activity relationship (SAR) studies, it is difficult if not impossible to predict how small chemical changes in ligand composition affects potency and efficacy (Fujioka et al 2012, Dosa et al 2016. There are also structural differences in how different ligand-binding proteins bind synthetic ligands that could influence potency-efficacy relationships.…”

N‐Arylsulfonyl Indolines as Retinoic Acid Receptor‐Related Orphan Receptor γ (RORγ) Agonists

“…More recently, modulators that bind to an allosteric site, distinct from the oxysterol pocket and containing elements of the activation function 2 (AF‐2) cleft on RORγ, like MRL871 (inverse agonist) and SR0987 (agonist), have been described . The identification of ligands with opposing pharmacology from within the same scaffold is not uncommon . Minor structural changes to the molecules can perturb receptor interactions altering hydrogen bond networks, leading to conformational changes that modulate interactions with coregulatory proteins.…”

“…[30] The identification of ligands with opposing pharmacology from within the same scaffold is not uncommon. [31] Minor structuralc hanges to the molecules can perturb receptori nteractions alteringh ydrogen bond networks, leading to conformationalc hanges that modulate interactions with coregulatory proteins.S tructuralc hanges may also impact post-translational modifications resulting in distinct pharmacological outcomes. During the development of RORg modulators, this has been reported on multiple occasions ( Figure 2).…”

Structural basis for selectivity and diversity in angiotensin II receptors

“…Both compounds are derivatives of a series of small-molecule antagonists of AT 1 R and thus could be assumed to exert the same function in AT 2 R. However, classification of compounds using traditional G protein-coupled receptor (GPCR) nomenclature into antagonists or agonists has proven difficult for AT 2 R since it has not been reliably demonstrated to signal through any of the canonical GPCR signaling pathways involving G proteins or β-arrestin. Furthermore, it has been observed numerous times that small changes to the structures of closely related compounds can lead to changes or bias in function 28,29 . Therefore, we refer to Cpd 1 and Cpd 2 using the neutral term ‘ligand’.…”