Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Str., 30-688 Kraków, Poland.
Univ. Grenoble Alpes, CNRS, CEA, IBS, F-38000 Grenoble, France.
J Med Chem. 2023 Nov 9;66(21):14928-14947. doi: 10.1021/acs.jmedchem.3c01482. Epub 2023 Oct 5.
The multifactorial origin and neurochemistry of Alzheimer's disease (AD) call for the development of multitarget treatment strategies. We report a first-in-class triple acting compound that targets serotonin type 6 and 3 receptors (5-HT-Rs) and monoamine oxidase type B (MAO-B) as an approach for treating AD. The key structural features required for MAO-B inhibition and 5-HTR antagonism and interaction with 5-HTR were determined using molecular dynamic simulations and cryo-electron microscopy, respectively. Bioavailable reversed scopolamine-induced cognitive deficits in the novel object recognition test. Furthermore, it displayed superior pro-cognitive properties compared to intepirdine (a 5-HTR antagonist) in the AD model, which involved intracerebroventricular injection of an oligomeric solution of amyloid-β peptide (oAβ) in the T-maze test in rats. , but not intepirdine, restored levels of biomarkers characteristic of the debilitating effects of oAβ. These data support the potential of a multitarget approach involving the joint modulation of 5-HTR/5-HTR/MAO-B in AD.
阿尔茨海默病（AD）的多因素起源和神经化学特性要求开发多靶点治疗策略。我们报告了一种首创的三作用化合物，该化合物靶向 5-羟色胺 6 型和 3 型受体（5-HT-Rs）和单胺氧化酶 B（MAO-B），作为治疗 AD 的一种方法。使用分子动力学模拟和冷冻电子显微镜分别确定了抑制 MAO-B 和 5-HTR 拮抗作用以及与 5-HTR 相互作用所需的关键结构特征。该化合物可逆转 scopolamine 诱导的认知缺陷，在新物体识别测试中表现出生物利用度。此外，与 intepirdine（5-HT 拮抗剂）相比，该化合物在 AD 模型中表现出更好的促认知特性，该模型涉及在大鼠 T 迷宫测试中脑室内注射淀粉样β肽（oAβ）的寡聚溶液。只有该化合物而不是 intepirdine，可恢复 oAβ 的衰弱作用的特征生物标志物的水平。这些数据支持涉及 5-HT-R/5-HT-R/MAO-B 联合调节的多靶点方法在 AD 中的潜力。
