Hybrid dopamine uptake blocker-serotonin releaser ligands: a new twist on transporter-focused therapeutics

ACS Med Chem Lett. 2014 Apr 15;5(6):623-7. doi: 10.1021/ml500113s. eCollection 2014 Jun 12.


As part of our program to study neurotransmitter releasers, we report herein a class of hybrid dopamine reuptake inhibitors that display serotonin releasing activity. Hybrid compounds are interesting since they increase the design potential of transporter related compounds and hence represent a novel and unexplored strategy for therapeutic drug discovery. A series of N-alkylpropiophenones was synthesized and assessed for uptake inhibition and release activity using rat brain synaptosomes. Substitution on the aromatic ring yielded compounds that maintained hybrid activity, with the two disubstituted analogues (PAL-787 and PAL-820) having the most potent hybrid activity.

Keywords: Dopamine uptake inhibitors; cocaine; methamphetamine; serotonin receptor; serotonin releasers.

Grants and funding

National Institutes of Health, United States