Uncovering Structure–Activity Relationships of Phenethylamines: Paving the Way for Innovative Mental Health Treatments

Abstract

The rapidly evolving psychedelic industry has garnered considerable attention due to 3,4-methylenedioxymethamphetamine-assisted psychotherapy's ground-breaking success in treating moderate-to-severe Post-traumatic Stress Disorder in two Phase 3 clinical trials. This has opened Pandora's box for the development of innovative therapeutic modalities. Of particular interest are the phenethylamines and their ability to inhibit monoamine transporters. In this study, we employed the quantitative structure− activity relationship methodology to develop three vigorous models for the reuptake of serotonin, dopamine, and norepinephrine through monoamine transporters. These models were thoroughly validated using various criteria, including fitting (R 2 DAT = 0.869, R 2 SERT = 0.828, and R 2 NET = 0.887), internal (Q 2 loo DAT = 0.795, Q 2 loo SERT = 0.784, and Q 2 loo NET = 0.820), and external (RMSEext DAT = 0.373, R 2 ext DAT = 0.831, RMSEext SERT = 0.200, R 2 ext SERT = 0.955, RMSEext NET = 0.318, and R 2 ext NET = 0.711) criteria.