Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonists.

Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonists. Sci Signal. 2020 Mar 31;13(625): Authors: Gillis A, Gondin AB, Kliewer A, Sanchez J, Lim HD, Alamein C, Manandhar P, Santiago M, Fritzw.er S, Schmidel F, Katte TA, Reekie T, Grimsey NL, Kassiou M, Kellam B, Krasel C, Halls ML, Connor M, Lane JR, Schulz S, Christie MJ, Canals M Abstract Biased agonism at G protein-coupled receptors describes the phenomenon whereby some drugs can activate some downstream signaling activities to the relative exclusion of others. Descriptions of biased agonism focusing on the differential engagement of G proteins versus β-arrestins are commonly limited by the small response windows obtained in pathways that are not amplified or are less effectively coupled to receptor engagement, such as β-arrestin recruitment. At the μ-opioid receptor (MOR), G protein-biased ligands have been proposed to induce less constipation and respiratory depressant side effects than opioids commonly used to treat pain. However, it is unclear whether these improved safety profiles are due to a reduction in β-arrestin-mediated signaling or, alternatively, to their low intrinsic efficacy in all signaling pathways. Here, we systematically evaluated the most recent and promising MOR-biased ligands and assessed their pharmacological profile against existing opioid analgesics in assays not confounded by limited signa...
Source: Science Signaling - Category: Biomedical Science Authors: Tags: Sci Signal Source Type: research