About Biased Signaling

G protein coupled receptors (GPCRs) transfer chemically encoded information across the cell membrane via multiple signaling pathways (Figure 1). Their abundance and their relevance in regulating the majority of (patho-) physiological processes in humans render them pharmacological targets for 35% of all currently marketed drugs [1]. In recent years, biased signaling (also referred to as functional selectivity) is an emerging issue in pharmacology and medicinal chemistry, since it holds the potential to specifically address signaling pathways linked to the desired therapeutic effect and exclude potential side effects [2]. However, little is known about structural ligand features leading to biased signaling, which makes rational design of such ligands an elusive task. In order to determine biased signaling of a ligand, it has to be measured in two different assays (representing different intracellular responses) and to be compared with a reference ligand.

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