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

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.