Structure–Activity Relationship and Evaluation of Phenethylamine and Tryptamine Derivatives for Affinity towards 5-Hydroxytryptamine Type 2A Receptor
Biomolecules & Therapeutics – October 13, 2022
Source: OpenAlex
Summary
Phenethylamines demonstrate a significantly higher affinity for the 5-HT<sub>2A</sub> receptor compared to tryptamines, with structural modifications impacting binding strength. In a study analyzing 14 receptor subtypes, phenethylamine derivatives showed promising results: specific alkyl or halogen groups on the phenyl ring enhanced binding when positioned para to the β carbon. Conversely, certain tryptamine modifications negatively influenced affinity. These findings, derived from functional evaluations of selected compounds, pave the way for developing new ligands targeting 5-HT<sub>2A</sub>R, potentially aiding in the treatment of psychiatric disorders and addiction.
Abstract
Among 14 subtypes of serotonin receptors (5-HTRs), 5-HT2AR plays important roles in drug addiction and various psychiatric disorders. Agonists for 5-HT2AR have been classified into three structural groups: phenethylamines, tryptamines, and ergolines. In this study, the structure-activity relationship (SAR) of phenethylamine and tryptamine derivatives for binding 5-HT2AR was determined. In addition, functional and regulatory evaluation of selected compounds was conducted for extracellular signal-regulated kinases (ERKs) and receptor endocytosis. SAR studies showed that phenethylamines possessed higher affinity to 5-HT2AR than tryptamines. In phenethylamines, two phenyl groups were attached to the carbon and nitrogen (R3) atoms of ethylamine, the backbone of phenethylamines. Alkyl or halogen groups on the phenyl ring attached to the β carbon exerted positive effects on the binding affinity when they were at para positions. Oxygen-containing groups attached to R3 exerted mixed influences depending on the position of their attachment. In tryptamine derivatives, tryptamine group was attached to the β carbon of ethylamine, and ally groups were attached to the nitrogen atom. Oxygen-containing substituents on large ring and alkyl substituents on the small ring of tryptamine groups exerted positive and negative influence on the affinity for 5-HT2AR, respectively. Ally groups attached to the nitrogen atom of ethylamine exerted negative influences. Functional and regulatory activities of the tested compounds correlated with their affinity for 5-HT2AR, suggesting their agonistic nature. In conclusion, this study provides information for designing novel ligands for 5-HT2AR, which can be used to control psychiatric disorders and drug abuse.