Superiority of the Triple-Acting 5‑HT6R/5-HT3R Antagonist and MAO‑B Reversible Inhibitor PZ-1922 over 5‑HT6R Antagonist Intepirdine in Alleviation of Cognitive Deficits in Rats

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-HT6R antagonism and interaction
with 5-HT3R were determined using molecular dynamic simulations
and cryo-electron microscopy, respectively. Bioavailable PZ-1922 reversed scopolamine-induced cognitive deficits in the novel object
recognition test. Furthermore, it displayed superior pro-cognitive
properties compared to intepirdine (a 5-HT6R 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. PZ-1922, 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-HT6R/5-HT3R/MAO-B in AD.

阿尔茨海默病（AD）的多因素起源及其神经化学特性迫切需要开发多靶点治疗策略。本研究报道了一种首创的三重作用化合物，该化合物针对5-羟色胺受体亚型6和3（5-HT-Rs）以及单胺氧化酶B型（MAO-B），作为治疗AD的新方法。通过分子动力学模拟和冷冻电子显微镜技术，分别确定了实现MAO-B抑制、5-HT6R拮抗及其与5-HT3R相互作用的关键结构特征。生物利用度高的PZ-1922能够逆转由东莨菪碱引起的认知缺陷，在新型物体识别测试中表现优异。此外，在阿尔茨海默病模型中，与intepirdine（一种5-HT6R拮抗剂）相比，PZ-1922显示出更优越的认知促进特性，该模型涉及在T迷宫测试大鼠脑室内注射由淀粉样β肽（oAβ）组成的低聚物溶液。PZ-1922而非intepirdine，能够恢复oAβ致病特征生物标志物的水平。这些数据支持了在AD中通过联合调节5-HT6R/5-HT3R/MAO-B实现多靶点治疗策略的潜力。