Serotonin Transporters (SERTs) are integral membrane proteins that transport serotonin from synaptic spaces into presynaptic neurons. SERTs function by reuptake serotonin in the synaptic cleft, effectively terminating the role of serotonin and halting neuronal transmission. Serotonin reuptake is a critical process to prevent the overstimulation of nerves. Many antidepressant medications of the serotonin reuptake inhibitor (SSRI) and tricyclic antidepressant classes work by binding to SERT and thus reducing serotonin reuptake.
ZZL-7 is a fast-onset antidepressant agent.
From: Sun N, et al. Science. 2022 Oct 28;378(6618):390-398.
ZZL-7 works by disrupting the interaction between the serotonin transporter (SERT) and neuronal nitric oxide synthase (nNOS) in the dorsal raphe nucleus (DRN). Structurally, ZZL-7 has advantageous structural characteristics: the acetylated amino of Ala of ZZL-7 formed an H-bond with Phe24 of nNOS; the carbonyl of Val of ZZL-7 made two H-bonds with the guanidino of Arg79 of nNOS. In vitro, ZZL-7 significantly decreases the SERT-nNOS complex level in 293T cells transfected with nNOS and SERT.
In addition, in vivo electrophysiology in SERT-Cre mice, ZZL-7 causes significantly increased firing frequency of serotonergic neurons 2 hours after treatment. Moreover, ZZL-7 reduces immobility time in wild-type mice as shown by tail suspension test (TST) and forced swimming test (FST) 2 hours after systematic administration, suggesting a fast antidepressant-like effect. ZZL-7 also causes a significantly decreased SERT-nNOS complex level and an increased cell surface SERT level in the DRN in wild-type but not in nNos−/− mice. Meanwhile, intragastric administration of ZZL-7 produces antidepressant-like behaviors dose-dependently 2 hours after treatment. Furthermore, ZZL-7 reverses the CMS-induced increase in the SERT-nNOS complex in the DRN and reverses CMS-induced depression behaviors. The fast-onset antidepressant effect persisted for at least 24 hours. Besides, ZZL-7 crosses the blood-brain barrier readily, and also penetrates the cellular membrane. Thus, ZZL-7 has the potential for major depressive disorder (MDD) research.
In summary, ZZL-7 is a fast-onset antidepressant agent and has the potential for MDD research.