Qualitative and quantitative assessment of relative agonist efficacy.
Historically, the ability of a ligand to bind to its receptor and the ability to subsequently activate that receptor have been described as the properties of affinity and intrinsic efficacy, respectively. These properties were originally believed to be independent of one another; both are possessed by ligands classed as "agonists," and they have served as the quantitative foundation of the drug and receptor classification process. Although affinity has been interpreted readily in physicochemical terms, equivalent molecular models for efficacy remain elusive. In recent times, there has been a significant paradigm shift in our understanding of the interrelationship between affinity and intrinsic efficacy, particularly on theoretical grounds, yet the actual methods available to measure these parameters remain largely operational. Nevertheless, a number of approaches, based on both functional measurements and radioligand binding studies, are available to quantify agonist efficacy on a relative scale and, to date, these remain the most practical. This commentary discusses the most common of these methods, their advantages and limitations, the dependence of the expression of agonism on the chosen assay system, and the impact of recent biochemical and molecular biological advances on the study of efficacy. Additionally, some of the more contemporary theories regarding the molecular nature of efficacy are briefly discussed, as well as the caveats that always must be borne in mind when any determinations of relative agonist efficacy are made.
Christopoulos
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Department of Pharmacology, University of Minnesota Medical School, Minneapolis 55455, USA.
El-Fakahany
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D000818:Animals; D001667:Binding, Competitive; D004305:Dose-Response Relationship, Drug; D005818:Genetic Engineering; D006801:Humans; D008954:Models, Biological; D011869:Radioligand Assay; D011956:Receptors, Cell Surface / Q000819:agonists*
D011956:Receptors, Cell Surface