In vitro and in vivo pharmacological characterization of dasotraline, a dual dopamine and norepinephrine transporter inhibitor in vivo

Rudy Schreiber*, Una Campbell, Maria S Quinton, Larry W Hardy, Q Kevin Fang, Robert Lew

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Inhibitors of dopamine transporters (DAT), norepinephrine transporters (NET) and serotonin transporters (SERT) are effective treatments for neuropsychiatric diseases. Dasotraline [(1R,4 S)- 4-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydro-1-naphthalenamine, also known as SEP-225289) was evaluated for its inhibitory potency at DAT, NET and SERT using in vitro and in vivo assays. In vitro radiometric functional uptake studies showed preferential inhibition by dasotraline of hDAT (IC50 =3 nM) and hNET (IC50 =4 nM relative to hSERT(IC50 =15 nM). In mouse ex vivo occupancy studies, dasotraline demonstrated total plasma concentration-dependent occupancy at DAT, NET and SERT. Determination of the TO50 (50% transporter occupancy) were 32, 109 and 276 ng/ml, respectively. In SPECT imaging studies in baboons, dasotraline (0.2 mg/kg iv) displaced radiotracer binding to DAT by 87% but only 20% at NET and SERT. Rat microdialysis studies were performed in prefrontal cortex and striatum. Dasotraline produced sustained (>4 h) increases in dopamine and norepinephrine concentrations. Dasotraline was also more potent at increasing synaptic dopamine in the striatum, and norepinephrine in the prefrontal cortex than serotonin in these regions. In summary, dasotraline preferentially inhibits DAT and NET relative to SERT. Together, the occupancy and neurochemical profile of dasotraline provide a mechanistic basis for the treatment of diseases that have an underlying causality involving dopamine and norepinephrine dysfunction.

Original languageEnglish
Article number113359
Number of pages10
JournalBiomedicine & Pharmacotherapy
Volume153
Early online date1 Jul 2022
DOIs
Publication statusPublished - Sept 2022

Keywords

  • ANTIDEPRESSANTS
  • ATTENTION-DEFICIT/HYPERACTIVITY DISORDER
  • BINDING
  • DEPRESSION
  • EXTRACELLULAR DOPAMINE
  • METHYLPHENIDATE
  • OCCUPANCY
  • PROFILE
  • RADIOLIGAND
  • SEROTONIN REUPTAKE INHIBITORS

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