Optimized 5-HT2b inhibitors for neuropsychiatric syndromes with cognitive dysfunction

Introduction: Neuropsychiatric syndromes such as anxiety and agitation are clinical presentations common to diverse neurodegenerative diseases and brain injury sequelae. They are a concern due to the impact on cognition, social interactions, and non-pharmacological treatments. Cognitive or behavioral disturbances occur at early disease stages and increase with disease progression. Coincident pathologies include the loss of serotonin (5-HT) neurons and appearance of neurofibrillary tangles in the raphe nucleus. Brain 5-HT_2b receptor (5-HT_2bR) levels are increased in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and post-stroke morbidity. HTR2B gene variants are implicated in psychiatric disorders. 5-HTRs are associated with atypical neurotropic drug mechanisms and behavioral dysfunction in drug abuse. The accumulating body of evidence suggests that selective 5-HT_2bR inhibition might mitigate neuropsychiatric syndromes and the associated cognitive dysfunction. Atypical neurotropic drugs interact with a variety of monoamine receptors and outcomes are viewed as a combination of 5-HT and dopamine D2 receptor mediated actions. Clearly, there is a need for insight into precision 5-HT_2bR inhibition as a potential pharmacological mechanism for treatment of neuropsychiatric syndromes and cognitive dysfunction associated with dementia.

Methods: Strategic optimization of an atypical neurotropic drug was used to develop MW073, a highly selective and orally bioavailable inhibitor of 5-HT_2bR activity and β-arrestin-1 recruitment that is devoid of Dopamine Receptor recognition and risk of 5-HT_2bR agonist activity.

Results: MW073 ameliorates amyloid and tau induction of behavioral dysfunction in preventive or disease stage intervention paradigms. Using MW073 as a standard of comparison, risperidone was shown to be a dose-dependent inhibitor 5-HT_2bR activity and β-arrestin-1 recruitment.

Discussion: Selective inhibition of 5-HT_2bR activity is a viable mechanism for the treatment of neuropsychiatric syndromes with synaptic dysfunction as a root cause and is a previously unrealized pharmacodynamic mechanism potentially embedded in current neurotherapeutics.

Highlights: A new highly selective 5-HT_2bR antagonist, MW073, is described and used as a reference standard.MW073 attenuates synaptic and behavioral dysfunctions an animal models of neuropsychatric syndromes.Risperidone is a dose dependent inhibitor of 5-HT_2bR activity and Arrestin recruitment.

5‐HT2B; Alzheimer's disease; Anxiety; G‐protein–coupled receptor serotonin receptors; aggression; atypical neurotherapeutics; cognitive dysfunction; depression; humans; irritability; memory; mental health; risperidone; synaptic plasticity; tauopathies.