Agonist binding, agonist affinity and agonist efficacy at G protein‐coupled receptors

• Published in: British journal of pharmacology 2008-04, Vol.153 (7), p.1353-1363
• Main Author: Strange, P G
• Format: Article
• Language: English
• Subjects: agonist affinity; agonist binding; agonist efficacy; Binding Sites; Biological and medical sciences; Drug Agonism; Drug Design; G protein‐coupled receptors; Humans; Ligands; Medical sciences; Models, Biological; Pharmacology. Drug treatments; Protein Binding; Receptors, G-Protein-Coupled - agonists; Reviews
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0707672

Measurements of affinity and efficacy are fundamental for work on agonists both in drug discovery and in basic studies on receptors. In this review I wish to consider methods for measuring affinity and efficacy at G protein coupled receptors (GPCRs). Agonist affinity may be estimated in terms of the dissociation constant for agonist binding to a receptor using ligand binding or functional assays. It has, however, been suggested that measurements of affinity are always contaminated by efficacy so that it is impossible to separate the two parameters. Here I show that for many GPCRs, if receptor/G protein coupling is suppressed, experimental measurements of agonist affinity using ligand binding (Kobs) provide quite accurate measures of the agonist microscopic dissociation constant (KA). Also in pharmacological functional studies, good estimates of agonist dissociation constants are possible. Efficacy can be quantitated in several ways based on functional data (maximal effect of the agonist (Emax), ratio of agonist dissociation constant to concentration of agonist giving half maximal effect in functional assay (Kobs/EC50), a combined parameter EmaxKobs/EC50). Here I show that EmaxKobs/EC50 provides the best assessment of efficacy for a range of agonists across the full range of efficacy for full to partial agonists. Considerable evidence now suggests that ligand efficacy may be dependent on the pathway used to assess it. The efficacy of a ligand may, therefore, be multidimensional. It is still, however, necessary to have accurate measures of efficacy in different pathways. British Journal of Pharmacology (2008) 153, 1353–1363; doi:10.1038/sj.bjp.0707672; published online 28 January 2008