Diverse chemotypes drive biased signaling by cannabinoid receptors

• DOI: 10.1101/2020.11.09.375162
• Publication Date: 2020-11-11T00:23:44Z
• Authors: Tamara Miljuš; Franziska M. Heyd...; Thais Gazzi; Atsushi Kimbara; Mark Rogers-Evans; Matthias Nettekoven; Elisabeth Zirwes; Anja Osterwald; Arne C. Rufer; Christoph Ullmer; Wolfgang Guba; Christian Le Gouill; Jürgen Fingerle; Marc Nazaré; Uwe Grether; Michel Bouvier; Dmitry B. Veprintsev
• Keywords: 0301 basic medicine; 03 medical and health sciences; Technology Platforms; 3. Good health

Abstract Cannabinoid CB1 and CB2 receptors are members of the G protein-coupled receptor family, which is largest class membrane proteins in human genome. As part endocannabinoid system, they have many regulatory functions body. Their malfunction therefore triggers a diverse set undesired conditions, such as pain, neuropathy, nephropathy, pruritus, osteoporosis, cachexia Alzheimer’s disease. Although drugs targeting system exist, molecular functional mechanisms involved still poorly understood, preventing development better therapeutics with fewer effects. One path toward safer medicines cannabinoid relies on ability some compounds to activate subset pathways engaged by while sparing or even inhibiting others, phenomenon known biased signaling. To take advantage this for drug development, profiling required. Using BRET-based signaling detection platform, we systematically analyzed primary cascades activated receptors, including 9 protein 2 β-arrestin subtypes. Given that driven ligand-specific distinct active conformations receptor, establishing link between profiles elicited different their chemotypes may help designing selectively beneficial avoiding those leading We screened selection 35 structurally ligands, endocannabinoids, phytocannabinoids synthetic similar significantly from natural cannabinoids. Our data show prominent feature that, predicted, ligands profiles. The study allows understanding provides information about tool can now be used biological outcomes, aiding design improved therapeutics.