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

Strange, P. G. (2008) Agonist binding, agonist affinity and agonist efficacy at G protein-coupled receptors. British Journal of Pharmacology, 153 (7). pp. 1353-1363. ISSN 0007-1188

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To link to this article DOI: 10.1038/sj.bjp.0707672

Abstract/Summary

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 (K-obs) provide quite accurate measures of the agonist microscopic dissociation constant (K-A). 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 (E-max), ratio of agonist dissociation constant to concentration of agonist giving half maximal effect in functional assay ( K-obs/ 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.

Item Type:Article
Refereed:Yes
Divisions:Faculty of Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy
ID Code:13631
Uncontrolled Keywords:agonist binding, agonist affinity, agonist efficacy, G protein-coupled, receptors, SITE-DIRECTED MUTAGENESIS, BETA-ADRENERGIC-RECEPTOR, MUSCARINIC, ACETYLCHOLINE-RECEPTOR, COMPLEX OCCUPANCY MECHANISMS, D-2, DOPAMINE-RECEPTOR, GTP-GAMMA-S, LIGAND-BINDING, TRANSMEMBRANE DOMAIN, ASPARTATE RESIDUE, ALPHA(2A)-ADRENERGIC RECEPTOR

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