Optimized 5-HT_2b inhibitors for neuropsychiatric syndromes with cognitive dysfunction

Area of Science:

• Neuroscience
• Pharmacology
• Neurodegenerative Diseases

Background:

• Neuropsychiatric syndromes like anxiety and agitation are common in neurodegenerative diseases and brain injuries.
• Serotonin (5-HT) neuron loss and increased 5-HT_2b receptor (5-HT_2bR) levels are observed in conditions like Alzheimer's disease.
• HTR2B gene variants are linked to psychiatric disorders, suggesting 5-HT_2bR as a therapeutic target.

Purpose of the Study:

• To investigate selective 5-HT_2bR inhibition as a potential treatment for neuropsychiatric syndromes and associated cognitive dysfunction.
• To develop and characterize MW073, a novel, selective, and orally bioavailable 5-HT_2bR antagonist.

Main Methods:

• Strategic optimization of an atypical neurotropic drug led to the development of MW073.
• MW073 was designed as a selective inhibitor of 5-HT_2bR activity and β-arrestin-1 recruitment, without dopamine receptor activity.
• MW073 was used as a reference standard to evaluate risperidone's effects on 5-HT_2bR activity.

Main Results:

• MW073 ameliorated behavioral dysfunction induced by amyloid and tau in animal models.
• MW073 demonstrated efficacy in both preventive and disease-stage intervention paradigms.
• Risperidone was confirmed as a dose-dependent inhibitor of 5-HT_2bR activity and β-arrestin-1 recruitment.

Conclusions:

• Selective 5-HT_2bR inhibition represents a viable therapeutic strategy for neuropsychiatric syndromes rooted in synaptic dysfunction.
• This approach offers a novel pharmacodynamic mechanism that may be leveraged by existing neurotherapeutics.
• MW073 serves as a valuable tool compound for further research into 5-HT_2bR-mediated pathways.