A Scale of Agonism and Allosteric Modulation for Assessment of Selectivity, Bias, and Receptor Mutation

• Published in: Molecular pharmacology Vol. 92; no. 4; p. 414
• Main Author: Kenakin, Terry
• Format: Journal Article
• Language: English
• Published: United States 01-10-2017
• Subjects: Allosteric Regulation - physiology; Animals; Dose-Response Relationship, Drug; Drug Agonism; Humans; Mutation - physiology; Protein Binding - physiology; Receptors, Cytoplasmic and Nuclear - agonists; Receptors, Cytoplasmic and Nuclear - metabolism; Signal Transduction - physiology; Structure-Activity Relationship
• ISSN: 1521-0111
• DOI: 10.1124/mol.117.108787

An index of agonism is described that can be used to quantify agonist receptor selectivity, bias, cell-based agonism, and the effects of receptor mutation on signaling. The parameter is derived from agonist concentration-response curves and comprises the maximal response to the agonist (max) and the EC
in the form of Δlog(max/EC
). This parameter is derived from equations describing agonists as positive allosteric facilitators of receptor-signaling protein interaction. A similar index is also derived to quantify the potentiating effects of positive allosteric modulators, which can be used to quantify in situ positive allosteric modulator activity in vivo. These indices lend themselves to statistical analysis and are system-independent in that the effects of the system processing of agonist response and differences in assay sensitivity and receptor expression are cancelled. The various applications of the Δlog(max/EC
) scale are described for each pharmacologic application.