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-HT(2A)R plays important roles in drug addiction and various psychiatric disorders. Agonists for 5-HT(2A)R 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-HT(2A)R 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-HT(2A)R 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 β 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 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-HT(2A)R, 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-HT(2A)R, suggesting their agonistic nature. In conclusion, this study provides information for designing novel ligands for 5-HT(2A)R, which can be used to control psychiatric disorders and drug abuse.