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ACS Chem Biol DOI:10.1021/acschembio.8b00168

Functionally Biased D2R Antagonists: Targeting the β-Arrestin Pathway to Improve Antipsychotic Treatment.

Publication TypeJournal Article
Year of Publication2018
AuthorsWeïwer, M, Xu, Q, Gale, JP, Lewis, M, Campbell, AJ, Schroeder, FA, Van de Bittner, GC, Walk, M, Amaya, A, Su, P, Ordevic, LD, Sacher, JR, Skepner, A, Fei, D, Dennehy, K, Nguyen, S, Faloon, PW, Perez, J, Cottrell, JR, Liu, F, Palmer, M, Pan, JQ, Hooker, JM, Zhang, Y-L, Scolnick, E, Wagner, FF, Holson, EB
JournalACS Chem Biol
Volume13
Issue4
Pages1038-1047
Date Published2018 04 20
ISSN1554-8937
KeywordsAnimals, Antipsychotic Agents, beta-Arrestins, Diagnostic Imaging, GTP-Binding Proteins, Humans, Locomotion, Mice, Receptors, Dopamine D2, Schizophrenia, Signal Transduction
Abstract

Schizophrenia is a severe neuropsychiatric disease that lacks completely effective and safe therapies. As a polygenic disorder, genetic studies have only started to shed light on its complex etiology. To date, the positive symptoms of schizophrenia are well-managed by antipsychotic drugs, which primarily target the dopamine D2 receptor (D2R). However, these antipsychotics are often accompanied by severe side effects, including motoric symptoms. At D2R, antipsychotic drugs antagonize both G-protein dependent (Gα) signaling and G-protein independent (β-arrestin) signaling. However, the relevant contributions of the distinct D2R signaling pathways to antipsychotic efficacy and on-target side effects (motoric) are still incompletely understood. Recent evidence from mouse genetic and pharmacological studies point to β-arrestin signaling as the major driver of antipsychotic efficacy and suggest that a β-arrestin biased D2R antagonist could achieve an additional level of selectivity at D2R, increasing the therapeutic index of next generation antipsychotics. Here, we characterize BRD5814, a highly brain penetrant β-arrestin biased D2R antagonist. BRD5814 demonstrated good target engagement via PET imaging, achieving efficacy in an amphetamine-induced hyperlocomotion mouse model with strongly reduced motoric side effects in a rotarod performance test. This proof of concept study opens the possibility for the development of a new generation of pathway selective antipsychotics at D2R with reduced side effect profiles for the treatment of schizophrenia.

DOI10.1021/acschembio.8b00168
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/29485852?dopt=Abstract

Alternate JournalACS Chem. Biol.
PubMed ID29485852