Development of Nitric Oxide Releasing Oxoisoaporphines with Antidepressant Activities by Simultaneously Regulating MAO-A and SERT,Journal of Medicinal Chemistry

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Development of Nitric Oxide Releasing Oxoisoaporphines with Antidepressant Activities by Simultaneously Regulating MAO-A and SERT
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-27 , DOI: 10.1021/acs.jmedchem.4c01161
Peisen Zhong ₁ , Xinyu Mao ₁ , Na Li ₁ , Li Chen ₁ , Jianbo Sun ₁

Affiliation

The occurrence of depression is closely related to the decrease in serotonin (5-HT) levels in the synaptic cleft. Designing negative regulators aiming at intervening in MAO-A and serotonin transporter (SERT) could work synergistically to elevate synaptic 5-HT levels and thus might exhibit superior antidepressant efficacy. By linking the lead compound oxoisoaporphine to various nitric oxide donors, we endeavored to design and synthesize 10 synergistic negative regulators. The overarching objective was to maintain the original inhibitory effect on MAO-A while concurrently mitigating SERT-mediated reuptake of 5-HT. Within the spectrum of inhibitory compounds, I₇ showcased the most formidable neuroprotective efficacy in a cellular depression model. In vivo experiments demonstrated that I₇ significantly improved depressive behavior in both zebrafish and mice. Further research indicated that the antidepressant mechanism of I₇ was associated with the downregulation of both MAO-A and SERT.

中文翻译：

通过同时调节 MAO-A 和 SERT 开发具有抗抑郁活性的释放一氧化氮的氧化异阿朴啡

抑郁症的发生与突触间隙血清素（5-HT）水平降低密切相关。设计旨在干预 MAO-A 和血清素转运蛋白 (SERT) 的负调节因子可以协同作用，提高突触 5-HT 水平，从而可能表现出卓越的抗抑郁功效。通过将先导化合物氧代异阿朴啡与各种一氧化氮供体连接，我们努力设计并合成了10种协同负调节剂。总体目标是维持对 MAO-A 的原始抑制作用，同时减轻 SERT 介导的 5-HT 重摄取。在一系列抑制化合物中， I ₇在细胞抑郁模型中表现出最强大的神经保护功效。体内实验表明， I ₇显着改善斑马鱼和小鼠的抑郁行为。进一步的研究表明， I ₇的抗抑郁机制与 MAO-A 和 SERT 的下调有关。

更新日期：2024-08-27

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