Science: Breakthrough! Chinese scholars have discovered a new target drug for depression, which has a rapid effect in 2 hours and no side effects

Depression is a common mental illness, and its incidence is increasing year by year, and it is prone to serious consequences
such as suicide.
The "monoamine hypothesis" is the theoretical basis of today's mainstream antidepressants, and the common disadvantage of such drugs is that they delay the onset of effect, and the classic antidepressant fluoxetine takes 2-4 weeks to begin to show its effect, which seriously hinders the acute treatment of patients with severe depression, and such drugs also have low efficiency, unstable efficacy, and some patients will even have aggravated symptoms and other problems
.

Early antidepressants monoamine oxidase (MAO) worked by inhibiting monoamine neurotransmitters in the synaptic cleft The degradation of tricyclic antidepressants (TCAs) inhibits the reuptake of monoamine neurotransmitters from the synaptic cleft, thereby increasing the concentration of monoamine neurotransmitters in the synaptic cleft to produce antidepressant effects
.
According to this, Sehildkraut JJ first proposed the catecholamine hypothesis of affective disorders, believing that the occurrence of depression is related
to the lack of catecholamines in the brain, especially NE (Norepinephrine, NE).
Subsequently, Coppen A found that serotonin dysfunction was associated with low mood and suicidal behavior, and subsequent findings on serotonin function in patients with depression led to the serotonin hypothesis
of depression.
In recent years, the progress of research on monoamine transmitters and corresponding receptors for depression is of great significance
for the pathogenesis of depression, especially the development of drugs.

Recently, researchers such as Zhou Qigang of Nanjing Medical University collaborated to design fast-acting antidepressants
by dislinking SERT and nNOS in DRN.
On October 28, a paper titled "Design of fast-onset antidepressant by dissociating SERT from nNOS in the DRN" was published in Science (Figure 1).

Figure 1 Research results (Source: Science)

The fast-acting antidepressant designed by the researchers works
by disrupting the interaction between the serotonin transporter (SERT) and neuronal nitric oxide synthase (nNOS) in the dorsal raphe nucleus (DRN).
。 The enhancement of SERT-nNOS interactions in DRN caused a depression-like phenotype and explained the depressive behavior caused by CMS (Chronic unpredictable mild stress), which can delay the onset of effect or even worsen depression
.
Disrupting the interaction of enzyme-coupled targets (SERT-nNOS) can produce a rapid antidepressant effect by enhancing serotonin signaling in the forebrain circuit independently of serotonin receptor desensitization (Figure 2).

Figure 2 Dissociating SERT from nNOS to design a fast-acting antidepressant (Source: Science).

The dorsal raphe nucleus (DRN) is the main source of
serotonin in the brain.
It projects to the cerebral cortex and limbic system and plays an important role
in regulating depressive moods.
Under physiological conditions, activation of somatic dendritic cells 5-HT1ARautos in DRN inhibits neural firing in serotonergic neurons, resulting in reduced
serotonin release from the cortex, HPC, and other parts of the brain.
In a depressive state, DRN 5-HT 1ARautos is highly active, resulting in a decrease in the firing frequency of serotonin neurons, a decrease in serotonin levels in the synaptic cleft, and inactivation
of postsynaptic 5-HT1ARheters.
SERT inhibitors simultaneously activate growth dendritic 5-HT 1ARauto and postsynaptic 5-HT1ARheters
.
Desensitization of 5-HT 1ARautos upsets the balance between 5-HT 1ARautos and 5-HT 1ARheters for weeks after treatment and induces antidepressant effects by postsynaptic 5-HT 1ARheters, suggesting that DRN5-HT/5- HT1ARauto signaling pathway enhancement is the main reason for the delayed onset of
action of SERT inhibitors.

The discovery of this new rapid antidepressant target is of revolutionary significance
to the classic hypothesis of depression, the monoamine hypothesis.
The research not only brings new insights into the classic theory of depression, the monoamine hypothesis, but also develops a fast-acting drug
candidate for depression.
The research team synthesized a rapid-acting antidepressant lead compound "ZZL-7", which showed that ZZL-7 can exert antidepressant effects after 2 hours of injection, and does not have the toxic side effects of other rapid antidepressants such as ketamine, which is suitable for a wide range of applications.

And it is possible to overcome the defect that third-generation antidepressants rely on serotonin self-receptor desensitization, and is expected to become a candidate for a whole new generation of antidepressants
.

This study overcame the third-generation antidepressant's reliance on serotonin autoreceptor desensitization, discovered a fast-acting antidepressant target, and updated the
monoamine hypothesis.
Professor Zhou Qigang said: "In the future, we will use ZZL-7 as the parent nuclear structure to synthesize a large number of compounds and conduct structure-activity relationship analysis, so as to screen out compounds with higher activity and good druggability, and carry out preclinical pharmaceutical research
.
”

Science highly praised the results and listed them as "Highlight"; International peers and media also highly praised the study, believing that this is a major theoretical breakthrough in antidepressant research in the 50 years since the discovery of the classic antidepressant fluoxetine in the nearly 60 years since the "monoamine hypothesis" was proposed.

Written by| Qiao Weijun

Typesetting| Muzijiu

Resources:

[1] Sun N, Qin YJ, Xu C, et al.
Design of fast-onset antidepressant by dissociating SERT from nNOS in the DRN.
Science.
2022 Oct 28; 378(6618):390-398.
doi: 10.
1126/science.
abo3566.
Epub 2022 Oct 27.
PMID: 36302033.

[2]https://xiaoban.
njmu.
edu.
cn/2022/1028/c5264a227609/page.
htm

[3] style="margin-bottom: 0px;white-space: normal;line-height: 1.
75em;visibility: visible;">[4]https://mp.
weixin.
qq.
com/s/1Pzoo4Rpi5e6tpPT_66LNA