**Background**
The Tropomyosin receptor kinase B (TrkB) is a high-affinity receptor for brain-derived neurotrophic factor (BDNF), playing a critical role in neuronal survival, differentiation, and synaptic plasticity. Dysregulation of the TrkB signaling pathway is closely linked to various neurological and psychiatric disorders, particularly major depressive disorder. Given its importance in maintaining cognitive function and mood stability, the discovery of small molecules that can mimic BDNF by activating TrkB is a significant goal for therapeutic development. In this context, we will introduce a potent TrkB activator and melatonin precursor – N-Acetyl-5-hydroxytryptamine.
**Definition**
N-Acetyl-5-hydroxytryptamine (NAS) is an endogenous metabolite and a precursor of melatonin that acts as a potent activator of the TrkB receptor.
**In Vitro and In Vivo Studies**
According to the N-Acetyl-5-hydroxytryptamine description, this compound is acetylated from serotonin by arylalkylamine N-acetyltransferase (AANAT). In terms of N-Acetyl-5-hydroxytryptamine in vitro activity, NAS swiftly activates the TrkB receptor in a circadian manner and exhibits antidepressant effects in a TrkB-dependent manner. Notably, it selectively activates TrkB without affecting TrkA or TrkC, and this activation occurs independently of neurotrophins and MT3 receptors. Additionally, in mouse B16 cells, it has been observed to inhibit catecholase activity of tyrosinase with an IC50 of 311 μM and demonstrate antimelanogenic activity with an IC50 > 30 μM.
To further evaluate N-Acetyl-5-hydroxytryptamine In Vivo, researchers utilized TrkB F616A knockin mice. In these models, TrkB F616A activation can be selectively blocked by 1NMPP1. Using cortical neurons from these mice, it was demonstrated that NAS-mediated TrkB phosphorylation is selectively reduced by 1NMPP1 but not by K252a. Furthermore, unlike serotonin or melatonin, NAS strongly provokes tyrosine phosphorylation and activation of both wild-type TrkB and TrkB F616A. This N-Acetyl-5-hydroxytryptamine biological activity suggests that NAS can effectively mimic the effects of BDNF. In conclusion, N-Acetyl-5-hydroxytryptamine is a potent TrkB receptor activator with significant potential for research into circadian rhythms and antidepressant therapies.
Keywords
N-Acetyl-5-hydroxytryptamine, 1210-83-9, N-Acetylserotonin, Normelatonin, O-Demethylmelatonin, Endogenous Metabolite, Trk Receptor, Tropomyosin related kinase receptor, Inhibitor, inhibitor, inhibit
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