Translating the atypical dopamine uptake inhibitor hypothesis toward therapeutics for treatment of psychostimulant use disorders

Neuropsychopharmacology. 2019 Jul;44(8):1435-1444. doi: 10.1038/s41386-019-0366-z. Epub 2019 Mar 11.


Medication-assisted treatments are unavailable to patients with cocaine use disorders. Efforts to develop potential pharmacotherapies have led to the identification of a promising lead molecule, JJC8-091, that demonstrates a novel binding mode at the dopamine transporter (DAT). Here, JJC8-091 and a structural analogue, JJC8-088, were extensively and comparatively assessed to elucidate neurochemical correlates to their divergent behavioral profiles. Despite sharing significant structural similarity, JJC8-088 was more cocaine-like, increasing extracellular DA concentrations in the nucleus accumbens shell (NAS) efficaciously and more potently than JJC8-091. In contrast, JJC8-091 was not self-administered and was effective in blocking cocaine-induced reinstatement to drug seeking. Electrophysiology experiments confirmed that JJC8-091 was more effective than JJC8-088 at inhibiting cocaine-mediated enhancement of DA neurotransmission. Further, when VTA DA neurons in DAT-cre mice were optically stimulated, JJC8-088 produced a significant leftward shift in the stimulation-response curve, similar to cocaine, while JJC8-091 shifted the curve downward, suggesting attenuation of DA-mediated brain reward. Computational models predicted that JJC8-088 binds in an outward facing conformation of DAT, similar to cocaine. Conversely, JJC8-091 steers DAT towards a more occluded conformation. Collectively, these data reveal the underlying molecular mechanism at DAT that may be leveraged to rationally optimize leads for the treatment of cocaine use disorders, with JJC8-091 representing a compelling candidate for development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cocaine / antagonists & inhibitors*
  • Cocaine / pharmacology
  • Dopamine / metabolism
  • Dopamine / pharmacology
  • Dopamine Antagonists / pharmacology
  • Dopamine Uptake Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug-Seeking Behavior / drug effects
  • Male
  • Molecular Docking Simulation
  • Nucleus Accumbens / metabolism
  • Oxalates / pharmacology*
  • Piperazines / pharmacology*
  • Rats
  • Self Administration
  • Synaptic Transmission / drug effects
  • Ventral Tegmental Area / drug effects


  • (1-(2-(bis(4-fluorophenyl)methoxy)ethyl)-4-(3-hydroxy-3-phenylpropyl) piperazinyl decanoate)
  • Dopamine Antagonists
  • Dopamine Uptake Inhibitors
  • JJC8-088
  • JJC8-091
  • Oxalates
  • Piperazines
  • Cocaine
  • Dopamine