Optimized 5-HT2b inhibitors for neuropsychiatric syndromes with cognitive dysfunction

IF 4.9 Q1 CLINICAL NEUROLOGY

Alzheimer''s and Dementia: Translational Research and Clinical Interventions Pub Date : 2025-03-27 DOI:10.1002/trc2.70073

Saktimayee M. Roy, Erica Acquarone, Elentina K. Argyrousi, Hong Zhang, Agnieszka Staniszewski, Asuka Inoue, Joshua J. Ziarek, Ottavio Arancio, D. Martin Watterson

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引用次数: 0

Abstract

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.

Abstract Image

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优化5-HT2b抑制剂治疗伴有认知功能障碍的神经精神综合征

神经精神综合征如焦虑和躁动是各种神经退行性疾病和脑损伤后遗症的常见临床表现。由于对认知、社会互动和非药物治疗的影响，它们引起了人们的关注。认知或行为障碍发生在疾病早期，并随着疾病进展而增加。相应的病理包括5-羟色胺（5-HT）神经元的丧失和中缝核神经原纤维缠结的出现。脑5-HT2b受体（5-HT2bR）水平在阿尔茨海默病（AD）、肌萎缩侧索硬化症（ALS）和卒中后发病率中升高。HTR2B基因变异与精神疾病有关。5-HTRs与药物滥用中的非典型嗜神经药物机制和行为障碍有关。越来越多的证据表明，选择性抑制5-HT2bR可能减轻神经精神综合征和相关的认知功能障碍。非典型嗜神经药物与多种单胺受体相互作用，其结果被视为5-HT和多巴胺D2受体介导作用的组合。显然，有必要深入了解精确的5-HT2bR抑制作为治疗与痴呆相关的神经精神综合征和认知功能障碍的潜在药理机制。方法通过对非典型嗜神经药物的策略优化，开发具有高选择性和口服生物利用度的5-HT2bR活性和β-arrestin-1募集抑制剂MW073，该抑制剂缺乏多巴胺受体识别和5-HT2bR激动剂活性的风险。结果MW073在预防或疾病阶段干预范式中改善淀粉样蛋白和tau诱导的行为功能障碍。以MW073作为对照标准，利培酮被证明是一种剂量依赖性的5-HT2bR活性和β-arrestin-1募集抑制剂。选择性抑制5-HT2bR活性是治疗以突触功能障碍为根本原因的神经精神综合征的一种可行机制，也是一种以前未实现的药效学机制，可能嵌入当前的神经治疗中。报道了一种新的高选择性5-HT2bR拮抗剂MW073，并将其作为参考标准。MW073减轻神经精神综合征动物模型的突触和行为功能障碍。利培酮是5-HT2bR活性和停搏蛋白募集的剂量依赖性抑制剂。

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来源期刊

Alzheimer''s and Dementia: Translational Research and Clinical Interventions Medicine-Psychiatry and Mental Health

CiteScore

10.10

自引率

2.10%

发文量

134

审稿时长

10 weeks

期刊介绍： Alzheimer''s & Dementia: Translational Research & Clinical Interventions (TRCI) is a peer-reviewed, open access,journal from the Alzheimer''s Association®. The journal seeks to bridge the full scope of explorations between basic research on drug discovery and clinical studies, validating putative therapies for aging-related chronic brain conditions that affect cognition, motor functions, and other behavioral or clinical symptoms associated with all forms dementia and Alzheimer''s disease. The journal will publish findings from diverse domains of research and disciplines to accelerate the conversion of abstract facts into practical knowledge: specifically, to translate what is learned at the bench into bedside applications. The journal seeks to publish articles that go beyond a singular emphasis on either basic drug discovery research or clinical research. Rather, an important theme of articles will be the linkages between and among the various discrete steps in the complex continuum of therapy development. For rapid communication among a multidisciplinary research audience involving the range of therapeutic interventions, TRCI will consider only original contributions that include feature length research articles, systematic reviews, meta-analyses, brief reports, narrative reviews, commentaries, letters, perspectives, and research news that would advance wide range of interventions to ameliorate symptoms or alter the progression of chronic neurocognitive disorders such as dementia and Alzheimer''s disease. The journal will publish on topics related to medicine, geriatrics, neuroscience, neurophysiology, neurology, psychiatry, clinical psychology, bioinformatics, pharmaco-genetics, regulatory issues, health economics, pharmacoeconomics, and public health policy as these apply to preclinical and clinical research on therapeutics.