Authors:	Michel, Martin C. Michel-Reher, Martina B. Hein, Peter
Title:	A systematic review of inverse agonism at adrenoceptor subtypes
Online publication date:	14-Dec-2020
Year of first publication:	2020
Language:	english
Abstract:	As many, if not most, ligands at G protein-coupled receptor antagonists are inverse agonists, we 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, the detection and degree of inverse agonism depend on the cells and tissues under investigation, i.e., they are greatest when the model has a high intrinsic tone/constitutive activity for the response being studied. Accordingly, they 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 is often low, leading to less consistent detection and a lesser extent of observed inverse agonism. Extent inverse agonism depends on specific molecular properties of a compound, but inverse agonism appears to be more common in certain chemical classes. While inverse agonism is a fascinating facet in attempts to mechanistically understand observed drug effects, we are skeptical whether an a priori definition of the 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
DDC:	570 Biowissenschaften 570 Life sciences
Institution:	Johannes Gutenberg-Universität Mainz
Department:	FB 04 Medizin
Place:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-5493
Version:	Published version
Publication type:	Zeitschriftenaufsatz
Document type specification:	Scientific article
License:	CC BY
Information on rights of use:	https://creativecommons.org/licenses/by/4.0/
Journal:	Cells 9 9
Pages or article number:	1923
Publisher:	MDPI
Publisher place:	Basel
Issue date:	2020
ISSN:	2073-4409
Publisher URL:	https://doi.org/10.3390/cells9091923
Publisher DOI:	10.3390/cells9091923
Appears in collections:	JGU-Publikationen