Structure–Activity Relationship and Evaluation of Phenethylamine and Tryptamine Derivatives for Affinity towards 5-Hydroxytryptamine Type 2A Receptor

The serotonin 2A receptor (5-HT2AR) is involved in drug addiction and psychiatric disorders. This study examined how the chemical structures of phenethylamine and tryptamine derivatives affect their binding to 5-HT2AR. Phenethylamines showed higher binding affinity than tryptamines. For phenethylamines, adding alkyl or halogen groups at the para position of the phenyl ring improved binding, while oxygen-containing groups had mixed effects depending on their position. For tryptamines, oxygen-containing groups on the larger ring increased affinity, but alkyl groups on the smaller ring and ally groups on the nitrogen decreased it. Functional tests indicated that compounds with higher affinity also showed stronger activation of signaling pathways and receptor internalization, suggesting they act as agonists. These findings guide the design of new 5-HT2AR ligands for treating psychiatric disorders and drug abuse.

Study at a glance

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.