title: In vivo veritas, the next frontier for functionally selective GPCR ligands.
abstract: The realization that G-protein coupled receptors (GPCR) engage several cell signaling mechanisms simultaneously has led to a multiplication of research aimed at developing biased ligands exerting a selective action on subsets of responses downstream of a given receptor. Several tools have been developed to identify such ligands using recombinant cell systems. However the validation of biased ligand activity in animal models remains a serious challenge. Here we present a general strategy that can be used to validate biased ligand activity in vivo and supports it as a strategy for further drug development. In doing so, we placed special attention on strategies allowing to discriminate between G-protein and beta-arrestin mediated mechanisms. We also underscore differences between in vitro and in vivo systems and suggest avenues for tool development to streamline the translation of biased ligands development to pre-clinical animal models.
authors: Dept. Psychiatry and Neuroscience, Faculty of Medicine, Laval University, Canada. Electronic address: martin.beaulieu.17@ulaval.ca.
authors: Jean Martin
authors: JM
authors: Beaulieu
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism* / Q000494:pharmacology; D006220:Haloperidol / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D011485:Protein Binding / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D008024:Ligands; D017448:Receptors, Dopamine D2; D043562:Receptors, G-Protein-Coupled; D000071557:beta-Arrestins; D006220:Haloperidol
keywords: Animal models; Beta-arrestin; Cell signaling; Functional selectivity; G protein coupled receptor