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

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 deter-mined. 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 (R-3) atoms of ethylamine, the backbone of phenethylamines. Alkyl or halogen groups on the phenyl ring attached to the 6 carbon exerted positive effects on the binding affinity when they were at para positions. Oxygen-containing groups attached to R-3 exerted mixed influences depending on the position of their attachment. In tryptamine derivatives, tryptamine group was attached to the 6 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.

Automated summary

The structure-activity relationship (SAR) of phenethylamine and tryptamine derivatives for binding 5-HT2AR was determined and functional and regulatory evaluation of selected compounds was conducted. Phenethylamines showed higher affinity to 5-HT2AR than tryptamines, with alkyl or halogen groups on the phenyl ring exerting positive effects on binding affinity in phenethylamines. Oxygen-containing groups on R-3 of phenethylamines had mixed influences. Oxygen-containing substituents on the large ring and alkyl substituents on the small ring of tryptamine groups had positive and negative influences, respectively.