Review
Version 1
Preserved in Portico This version is not peer-reviewed
A Systematic Review of Inverse Agonism at Adrenoceptor Subtypes
Version 1
: Received: 3 August 2020 / Approved: 4 August 2020 / Online: 4 August 2020 (16:01:12 CEST)
A peer-reviewed article of this Preprint also exists.
Michel, M.C.; Michel-Reher, M.B.; Hein, P. A Systematic Review of Inverse Agonism at Adrenoceptor Subtypes. Cells 2020, 9, 1923. Michel, M.C.; Michel-Reher, M.B.; Hein, P. A Systematic Review of Inverse Agonism at Adrenoceptor Subtypes. Cells 2020, 9, 1923.
Abstract
As many if not most ligands at G protein-coupled receptor antagonists are inverse agonists, we have systematically reviewed inverse agonism at the nine adrenoceptor subtypes. Except for β3-adrenoceptors, inverse agonism has been reported for each of the adrenoceptor subtypes, most often for β2-adrenoceptors, including endogenously expressed receptors in human tissues. As with other receptors, detection and degree of inverse agonism depends on the cells and tissues under investigation, i.e. is greatest when the model has a high intrinsic tone/constitutive activity for the response being studied. Accordingly, it may differ between parts of a tissue, for instance atria vs. ventricles of the heart, and within a cell type between cellular responses. The basal tone of endogenously expressed receptors often is low, leading to less consistent detection and smaller extent of observed inverse agonism. The extent inverse agonism depends on specific molecular properties of a compound but clusters by chemical class. While inverse agonism is a fascinating facet in attempts to mechanistically understand observed drug effects, we are skeptical whether an a priori definition of extent of inverse agonism in the target product profile of a developmental candidate is a meaningful option in drug discovery and development.
Keywords
adrenoceptor; constitutive activity; drug development; inverse agonism
Subject
Medicine and Pharmacology, Pharmacology and Toxicology
Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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