Procognitive Potential of Neuroprotective Triazine 5-HT6 Receptor Antagonists Tested on Chronic Activity In Vivo in Rats: Computer-Aided Insight into the Role of Chalcogen-Differences on the Pharmacological Profile.

IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
ACS Chemical Neuroscience Pub Date : 2025-03-19 Epub Date: 2025-02-28 DOI:10.1021/acschemneuro.4c00873
Magdalena Jastrzębska-Więsek, Sabrina Garbo, Agnieszka Cios, Natalia Wilczyńska-Zawal, Anna Partyka, Ewelina Honkisz-Orzechowska, Ewa Żesławska, Jarosław Handzlik, Barbara Mordyl, Monika Głuch-Lutwin, Alessia Raucci, Marius Hittinger, Małgorzata Starek, Monika Dąbrowska, Wojciech Nitek, Tadeusz Karcz, Alicja Skórkowska, Joanna Gdula-Argasińska, Kinga Czarnota-Łydka, Patryk Pyka, Ewa Szymańska, Katarzyna Kucwaj-Brysz, Clemens Zwergel, Anna Wesołowska, Cecilia Battistelli, Jadwiga Handzlik
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引用次数: 0

Abstract

Among serotonin receptors, the 5-HT6 subtype is an important protein target and its ligands may play a key role in the innovative treatment of cognitive disorders. This study aimed to extend the body of preclinical research on two naphthyl-derived methylpiperazine-1,3,5-triazine analogues with thioether (WA-22) or Se-ether (PPK-32) linkers, the newly described compounds having high affinity and selectivity for 5-HT6 receptors and drug-like parameters in vitro. Thus, crystallography-supported deeper insight into their chemical properties, the comparison of their neuroprotective and pharmacokinetic profiles, and especially their impact on memory disturbances after chronic administration to rats were investigated. As a result, the chronic administration of WA-22 completely reversed (+)MK-801-induced memory disturbances evaluated in the novel object recognition test (NORT) in rats. The pharmacokinetic and biochemical results support the notion that this 1,3,5-triazine 5-HT6 receptor ligand could offer a promising therapeutic tool in CNS-related disorders. The selenium compound PPK-32, with a similar range of activity at acute administration, has shown even broader neuroprotective profiles, especially at the genetic level. However, for therapeutic use, its weaker pharmacokinetics (stability), which is a probable limit for action upon chronic administration, would require improvement, e.g., by an appropriate formulation.

神经保护三嗪5-HT6受体拮抗剂在大鼠体内慢性活性测试中的前认知潜力:计算机辅助研究硫离子差异在药理学谱中的作用。
在5-羟色胺受体中,5-HT6亚型是一个重要的蛋白靶点,其配体可能在认知障碍的创新治疗中发挥关键作用。本研究旨在扩展两种萘衍生的甲基哌嗪-1,3,5-三嗪类似物与硫醚(WA-22)或硒醚(PPK-32)连接体的临床前研究,新描述的化合物对5-HT6受体和药物样参数具有高亲和力和选择性。因此,晶体学支持了对其化学性质的更深入的了解,比较了它们的神经保护和药代动力学特征,特别是它们对大鼠慢性给药后记忆障碍的影响。结果,在新对象识别测试(NORT)中,长期给药WA-22完全逆转(+)mk -801诱导的大鼠记忆障碍。药代动力学和生化结果支持这种1,3,5-三嗪5-HT6受体配体可能为中枢神经系统相关疾病提供有前途的治疗工具的观点。硒化合物PPK-32在急性给药时具有类似的活性范围,显示出更广泛的神经保护作用,特别是在遗传水平上。然而,对于治疗用途,其较弱的药代动力学(稳定性),这可能是慢性给药的作用限制,需要改进,例如通过适当的配方。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
ACS Chemical Neuroscience
ACS Chemical Neuroscience BIOCHEMISTRY & MOLECULAR BIOLOGY-CHEMISTRY, MEDICINAL
CiteScore
9.20
自引率
4.00%
发文量
323
审稿时长
1 months
期刊介绍: ACS Chemical Neuroscience publishes high-quality research articles and reviews that showcase chemical, quantitative biological, biophysical and bioengineering approaches to the understanding of the nervous system and to the development of new treatments for neurological disorders. Research in the journal focuses on aspects of chemical neurobiology and bio-neurochemistry such as the following: Neurotransmitters and receptors Neuropharmaceuticals and therapeutics Neural development—Plasticity, and degeneration Chemical, physical, and computational methods in neuroscience Neuronal diseases—basis, detection, and treatment Mechanism of aging, learning, memory and behavior Pain and sensory processing Neurotoxins Neuroscience-inspired bioengineering Development of methods in chemical neurobiology Neuroimaging agents and technologies Animal models for central nervous system diseases Behavioral research
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