HOMOAMPHETAMINES: STRUCTURAL OPTIMIZATION OF MONOAMINE TRANSPORTER FUNCTION TO MITIGATE ABUSE LIABILITY AND ENHANCE THERAPEUTIC SAFETY

Amphetamines are widely used psychostimulants that act by reversing the function of monoamine transporters, leading to increased extracellular levels of dopamine, norepinephrine, and serotonin. While clinically effective for disorders such as ADHD, narcolepsy, and PTSD, their use is associated with significant side effects including addiction, cardiovascular risks, and neuropsychiatric symptoms. The pharmacological profile of amphetamines is strongly influenced by structural modifications, which alter their interactions with the monoamine transporters. To address the need for safer therapeutics, this study explores novel analogs called homoamphetamines designed to enhance transporter selectivity and reduce adverse effects. Fourteen homoamphetamine analogs were synthesized through structural modifications of the amphetamine scaffold. Their pharmacological activity was assessed using uptake inhibition assays to determine inhibitory potency and release assays to evaluate their capacity to induce neurotransmitter efflux, which allowed for the characterization of each compound’s selectivity and mode of action. All fourteen compounds displayed varying degrees of transporter affinity and releasing activity. Several analogs showed high selectivity for specific monoamine transporters, with distinct profiles separating uptake inhibition from release functions. Some compounds acted primarily as uptake inhibitors, while others exhibited potent releasing properties. These variations in transporter interaction suggest the potential for selectively targeting monoamine systems while minimizing side effects commonly associated with non-selective amphetamines.The findings support that by tuning structural features it is possible to modulate the pharmacodynamics of amphetamine-like compounds, which could lead to the development of safer, more targeted psychostimulant therapies. Future work will involve in vivo validation of these profiles to confirm therapeutic relevance.