Abstract
Depression is a multifactorial disorder that affects millions of people worldwide, and none of the currently available therapeutics can completely cure it. Thus, there is a need for developing novel, potent, and safer agents. Recent medicinal chemistry findings on the structure and function of the serotonin 2A (5-HT2A) receptor facilitated design and discovery of novel compounds with antidepressant action. Eligible papers highlighting the importance of 5-HT2A receptors in the pathomechanism of the disorder were identified in the content-screening performed on the popular databases (PubMed, Google Scholar). Articles were critically assessed based on their titles and abstracts. The most accurate papers were chosen to be read and presented in the manuscript. The review summarizes current knowledge on the applicability of 5-HT2A receptor signaling modulators in the treatment of depression. It provides an insight into the structural and physiological features of this receptor. Moreover, it presents an overview of recently conducted virtual screening campaigns aiming to identify novel, potent 5-HT2A receptor ligands and additional data on currently synthesized ligands acting through this protein.
Highlights
In the case of animals euthanized 7-days post injections, in their brains, there was a significant increase in SV2A density in both prefrontal cortex and hippocampus, whereas no differences in density of 5-HT2A receptors were discovered. These results suggest that psilocybin causes persistent synaptogenesis and a noticeable decline in 5-HT2A receptor density, which may be correlated with its antidepressant properties [71]
Retrieved complexes were docked to the structure of the 5-HT2A receptor and evaluated with the use of molecular dynamics (MD) methods. This experiment resulted in the identification of several residues important for the ligand binding and 287 potential 5-HT2A receptor antagonists that may be submitted into additional experimental validation [88]
We summarized fundamental knowledge on the structure and functions of the 5-HT2A receptor
Summary
Medicinal therapeutical effectiveness of serotonin concentration modulators in the treatment of chemistry findings and pharmacological data highlight the therapeutical effectiveness of mood disorders. Within the CNS, this substance is released into the synaptic cleft and binds to specific proteins to activate 5-HT receptors located on postsynaptic neurons or serotonin autoreceptors located on the presynaptic part of the neuronal membrane. Serotonin and its receptors are believed to regulate, e.g., sexual behavior [15], mood [16], cognition [17], appetite [18], anxiety [8], aggression [19], the release of other neurotransmitters, addiction development [20], and sleep-wake cycles [21]. A brief overview of the recent application of virtual screening campaigns in the development of novel 5-HT ligands is provided
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