Being mindful of seven‐transmembrane receptor ‘guests’ when assessing agonist selectivity

Abstract

The time-honored approach of quantifying agonist selectivity through measurement of agonist affinity with binding and efficacy through potency ratios in model assays for prediction of effect in therapeutic systems can fall short of providing useful answers for functionally selective agonists. Agonists are now known to have pluridimensional efficacies that are associated with selected signalling pathways coupled to the receptor. This necessitates specifically tailored assay formats to measure predetermined efficacies of ligands to characterize agonist selectivity fully. If such assays can access signalling that directly emanates from the interaction of the agonist-bound receptor and a cytosolic signalling protein, then the Black/Leff operational model can be used to specifically quantify 'transduction ratios' (t/KA) that fully characterize selective activation of signalling pathways by a given agonist. As whole-cell processing of pleiotropic signalling cascades imposes cell-specific phenotypic agonist profiles, ultimately the assessment of agonist selectivity is most reliably done in the therapeutically relevant primary cell system. (2010) The paper in this issue of the BJP by Jillian Baker (Baker, 2010) emphasizes the importance of determining both the affinity and efficacy of selective agonists in assessing overall selectivity of agonism. The value of this approach in determining agonist receptor selectivity is clear, as agonist potency can be controlled by affinity or efficacy, or both. This basic pharmacological principle can be extended in light of our present knowledge of pleiotropic signalling through seven transmembrane receptors (7TMRs). Specifically, it is apparent that agonists activating receptors coupled to multiple signalling proteins can produce biased activation of some signalling pathways over others (see Kenakin, 2006;Mailman, 2007). Under these circumstances, conventional whole-cell measures of affinity (binding) and efficacy (whole-cell potency ratios) can be misleading. It is therefore worth discussing the concept of agonist selectivity in the functionally selective world. 7TMRs are allosteric systems mediating the vectorial transduction of energy from one locus on the receptor to another. Figure 1 Classical allosteric system for 7TMR agonism. All agonists become the 'modulator', the receptor is the 'conduit' and the cytosolic signalling molecules are the 'guests'. Within this scheme, the Black/Leff operational model can be used to quantify selective activation of pathways through identification of unique log(t/KA) ratios. British Journal of Pharmacology

Label-free integrative pharmacology on-target of opioid ligands at the opioid receptor family

“…First, different ligands often display a wide range of affinities binding to a specific receptor, and a specific ligand often displays distinct affinities binding to different opioid receptors (Additional file 1). Furthermore, the binding affinity of a ligand often does not directly translate to its potency to activate the receptor at the whole cell level [27,28], so it is practically difficult to choose ligand-specific concentrations for our systematic profiling. Second, the main purpose of the present study is to determine both binding and functional selectivity of the same family of ligands against the opioid receptor family, and almost all ligands examined displayed agonist activity in at least one of the five cell lines profiled (see results below).…”

Investigation of D2 Receptor–Agonist Interactions Using a Combination of Pharmacophore and Receptor Homology Modeling

“… 39 In addition, the receptors can adopt several different activated conformations and can also perform non-G-protein-mediated signaling via, for example, β-arrestin pathways, resulting in a range of effects. 40 – 42 Concepts such as functional selectivity and biased ligands have emerged and will most likely influence future pharmacological assay design 43 , 44 as well as drug discovery efforts directed toward these targets. 45 However, functional selectivity of agonists should not be confused with agonist receptor-subtype selectivity, which is the focus of this study.…”

Biased Ligands for Better Cardiovascular Drugs

“…Several attempts have been made to standardize nomenclature and criteria for determining ligand bias, 71,134 and recently several groups have introduced quantitative methods to assess ligand bias. [135][136][137] Further effort to develop these approaches is warranted, as is diligence in recognizing their assumptions and applying their criteria, to most efficiently move the field of ligand bias and functional selectivity forward to clinical relevance.…”