MW073

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 2b R) 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 2b R 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 2b R inhibition as a potential pharmacological mechanism for treatment of neuropsychiatric syndromes and cognitive dysfunction associated with dementia.

Strategic optimization of an atypical neurotropic drug was used to develop MW073, a highly selective and orally bioavailable inhibitor of 5‐HT 2b R activity and β‐arrestin‐1 recruitment that is devoid of dopamine receptor recognition and risk of 5‐HT 2b R agonist activity.

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 2b R activity and β‐arrestin‐1 recruitment.

Selective inhibition of 5‐HT 2b R 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.

A new highly selective 5‐HT 2b R 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 2b R activity and arrestin recruitment.