2 research outputs found
Legislative Documents
Also, variously referred to as: House bills; House documents; House legislative documents; legislative documents; General Court documents
Functionally Biased D2R Antagonists: Targeting the β‑Arrestin Pathway to Improve Antipsychotic Treatment
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<sub>i/o</sub>) 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 <b>BRD5814</b>, a highly brain penetrant β-arrestin
biased D2R antagonist. <b>BRD5814</b> demonstrated good target
engagement <i>via</i> 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