Characterization of the neurochemical and behavioral effects of solriamfetol (JZP-110), a selective dopamine and norepinephrine reuptake inhibitor

Michelle G. Baladi, Michael J. Forster, Michael B. Gatch, Richard B. Mailman, Danielle L. Hyman, Lawrence P. Carter, Aaron Janowsky

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Excessive sleepiness (ES) is associated with several sleep disorders, including narcolepsy and obstructive sleep apnea (OSA). A role for monoaminergic systems in treating these conditions is highlighted by the clinical use of US Food and Drug Administration–approved drugs that act on these systems, such as dextroamphetamine, methylphenidate, modafinil, and armodafinil. Solriamfetol (JZP-110) is a wake-promoting agent that is currently being evaluated to treat ES in patients with narcolepsy or OSA. Clinical and preclinical data suggest that the wake-promoting effects of solriamfetol differ from medications such as modafinil and amphetamine. The goal of the current studies was to characterize the mechanism of action of solriamfetol at monoamine transporters using in vitro and in vivo assays. Results indicate that solriamfetol has dual reuptake inhibition activity at dopamine (DA; IC50 5 2.9 mM) and norepinephrine (NE; IC50 5 4.4 mM) transporters, and this activity is associated in vivo with increased extracellular concentration of DA and NE as measured by microdialysis. Solriamfetol has negligible functional activity at the serotonin transporter (IC50 . 100 mM). Moreover, the wake-promoting effects of solriamfetol are probably owing to activity at DA and NE transporters rather than other neurotransmitter systems, such as histamine or orexin. The dual activity of solriamfetol at DA and NE transporters and the lack of significant monoamine-releasing properties of solriamfetol might explain the differences in the in vivo effects of solriamfetol compared with modafinil or amphetamine. Taken together, these data suggest that solriamfetol may offer an important advancement in the treatment of ES in patients with narcolepsy or OSA.

Original languageEnglish (US)
Pages (from-to)367-376
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume366
Issue number2
DOIs
StatePublished - Aug 1 2018

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Dopamine Uptake Inhibitors
Narcolepsy
Obstructive Sleep Apnea
Inhibitory Concentration 50
Norepinephrine
Amphetamine
Wakefulness-Promoting Agents
Serotonin Plasma Membrane Transport Proteins
Dextroamphetamine
Methylphenidate
Microdialysis
Pharmaceutical Preparations
Histamine
Neurotransmitter Agents
Dopamine
Food
modafinil
Therapeutics

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Characterization of the neurochemical and behavioral effects of solriamfetol (JZP-110), a selective dopamine and norepinephrine reuptake inhibitor. / Baladi, Michelle G.; Forster, Michael J.; Gatch, Michael B.; Mailman, Richard B.; Hyman, Danielle L.; Carter, Lawrence P.; Janowsky, Aaron.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 366, No. 2, 01.08.2018, p. 367-376.

Research output: Contribution to journalArticle

Baladi, Michelle G. ; Forster, Michael J. ; Gatch, Michael B. ; Mailman, Richard B. ; Hyman, Danielle L. ; Carter, Lawrence P. ; Janowsky, Aaron. / Characterization of the neurochemical and behavioral effects of solriamfetol (JZP-110), a selective dopamine and norepinephrine reuptake inhibitor. In: Journal of Pharmacology and Experimental Therapeutics. 2018 ; Vol. 366, No. 2. pp. 367-376.
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