Molecular docking analysis of amphetamines at sigma and trace amine-associated receptors

Amphetamine and structurally related compounds, including Adderall (amphetamine and dextroamphetamine salts), are widely used medications and illicit substances with high abuse potential, contributing to a global public health crisis. These compounds induce a substantial increase in dopamine release, leading to pronounced euphoria, heightened alertness, and increased energy. Chronic exposure is associated with reduced receptor sensitivity and decreased neuronal firing, resulting in neurotoxicity comparable to traumatic brain injury. In this study, we investigate the binding properties of N-methylamphetamine, 3,4-methylenedioxy-methamphetamine (MDMA), and 3,4-methylenedioxyamphetamine with sigma receptors and trace amine-associated receptor 1 (TAAR1) using computational approaches. Molecular docking simulations were employed to characterize ligand-receptor interactions, binding affinities, and inhibition constants, providing mechanistic insights into the differential engagement of these psychoactive compounds with key neural targets. These findings advance our understanding of the molecular determinants underlying amphetamine-related neuropharmacology and may inform therapeutic strategies for mitigating neurotoxic effects.