Prolintane analogs as hybrid monoamine transporter ligands: Structural determinants and species differences

Prolintane is a synthetic stimulant that acts by inhibiting the uptake of dopamine and norepinephrine into neurons. Initially prescribed for attention deficit hyperactivity disorder and narcolepsy, its medical use was discontinued due to concerns about abuse liability. Here, we explored structure-activity relationships for novel fluoro and methyl-ring-substituted prolintanes synthesized via a modified one-pot Mannich Barbier reaction. Radiotracer flux assays in transfected human embryonic kidney 293 (HEK293) cells and rat brain synaptosomes revealed that prolintane analogs display potent uptake inhibition at the dopamine transporter (DAT) and norepinephrine transporter (NET), with weaker effects at the serotonin transporter (SERT). Across all compounds, SERT inhibitory potencies were at least 10-fold weaker at human SERT (hSERT) compared to rat SERT (rSERT). Methyl substitution at the 2-, 3-, or 4-ring position enhanced SERT inhibition potency relative to DAT, lowering the DAT/SERT ratio and suggesting reduced abuse liability. Fluorine substitution also enhanced SERT potency relative to DAT, however, to a lesser extent. Interestingly, prolintane and its analogs induced hSERT-mediated ionic currents and [³H]serotonin efflux, which was not seen in rat brain synaptosomes. Overall, these findings indicate that prolintane analogs act as potent DAT and NET inhibitors, but they can also act as substrates and evoke serotonin release in cells expressing hSERT, classifying them as hybrid compounds at human monoamine transporters. Our study demonstrates how ring modifications alter prolintane pharmacology, emphasizing the need for future investigations into therapeutic and adverse effects of these compounds. Moreover, the species difference in SERT-releasing activity for prolintane analogs warrants further research.