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

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

  • ACS Chem Biol. 2018 Apr 20;13(4):1038-1047. doi: 10.1021/acschembio.8b00168.
Michel Weïwer 1,  Qihong Xu 1,  Jennifer P Gale 2,  Michael Lewis 1,  Arthur J Campbell 1,  Frederick A Schroeder 3,  Genevieve C Van de Bittner 3,  Michelle Walk 1,  Aldo Amaya 1,  Ping Su 4,  Luka D Ordevic 1,  Joshua R Sacher 1,  Adam Skepner 2,  David Fei 2,  Kelly Dennehy 1,  Shannon Nguyen 1,  Patrick W Faloon 2,  Jose Perez 2,  Jeffrey R Cottrell 1,  Fang Liu 4,  Michelle Palmer 2,  Jen Q Pan 1,  Jacob M Hooker 3,  Yan-Ling Zhang 1,  Edward Scolnick 1,  Florence F Wagner 1,  Edward B Holson 1
Affiliations

Affiliations

  • 1 Stanley Center for Psychiatric Research , Broad Institute of MIT and Harvard , Cambridge , Massachusetts 02142 , United States.
  • 2 Center for the Development of Therapeutics , Broad Institute of MIT and Harvard , Cambridge , Massachusetts 02142 , United States.
  • 3 Department of Radiology, MGH , Athinoula A. Martinos Center for Biomedical Imaging , Charlestown , Massachusetts 02129 , United States.
  • 4 Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health , University of Toronto , Toronto , Ontario M5T1R8 , Canada.
PMID: 29485852 DOI: 10.1021/acschembio.8b00168
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 (Gαi/o) 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.

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