In Silico Evaluation of Tryptamine-Derived Schiff Bases as Modulators of the Serotonin 5-HT₂A Receptor

Abstract

Serotonin receptors, also known as 5-hydroxytryptamine (5-HT) receptors, are a diverse family of G protein-coupled and ligand-gated ion channel receptors that mediate the physiological effects of the neurotransmitter serotonin. These receptors are widely distributed throughout the central and peripheral nervous systems, where they regulate numerous processes including mood, cognition, thermoregulation, appetite, and gastrointestinal function. To date, seven distinct receptor families (5-HT₁ to 5-HT₇) comprising multiple subtypes have been identified, each exhibiting unique pharmacological profiles, signal transduction mechanisms, and tissue-specific expression. Due to their broad functional relevance, serotonin receptors are key therapeutic targets in the treatment of neuropsychiatric disorders such as depression, anxiety, schizophrenia, and migraine. Continued investigation into their structure-function relationships, signaling pathways, and ligand specificity holds significant promise for the development of more selective and effective pharmacological agents. The 5-HT₂A receptor is one of the most extensively studied subtypes of the serotonin receptor family due to its prominent role in both normal physiology and various neuropsychiatric conditions. The 5-HT₂A receptor is highly expressed in the cerebral cortex, especially in pyramidal neurons of the prefrontal cortex, where it plays a critical role in modulating perception, cognition, and mood. It has been implicated in the pathophysiology of disorders such as schizophrenia, depression, and anxiety, and is the principal target of many atypical antipsychotics and hallucinogenic compounds, including LSD and psilocybin. Activation of 5- HT₂A receptors by psychedelic agents is thought to underlie their profound effects on consciousness, suggesting a central role for this receptor in shaping subjective experience and higher-order cognitive functions. Ongoing research is exploring the therapeutic potential of selective 5-HT₂A modulation in treating mood disorders and facilitating psychotherapy, while also investigating the complex signaling pathwys and receptor interactions that influence its pharmacology. In this study, molecular docking was performed to investigate the binding interactions of a series of tryptamine-based Schiff base compounds with the 5-HT₂A receptor. The three-dimensional structure of the receptor was obtained from available crystallographic data and prepared by refining the active site and removing any co-crystallized ligands. Ligands were constructed and energy-minimized using standard force fields to ensure accurate conformations for docking. Docking simulations were conducted using AutoDock Vina, with a defined grid box centered on the orthosteric binding site known to accommodate serotonin and related ligands. The docking data were analyzed to identify key hydrogen bonding, π-π stacking, and hydrophobic contacts between the Schiff base ligands and crucial residues of the 5-HT₂A receptor in order to provide better insight into structure-activity relationships and offer a foundation for rational design of novel serotonergic ligands with potential psychoactive or therapeutic properties. The results have shown that quinoline-based Schiff base expressed the highest affinity towards the receptor, even greater than the known agonist serotonin, LSD and psilocybin.