New Insights into the Mechanism of Action of Viloxazine: Serotonin and Norepinephrine Modulating Properties.
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Yu C, Garcia-Olivares J, Candler S, Schwabe S, Maletic V
New Insights into the Mechanism of Action of Viloxazine: Serotonin and Norepinephrine Modulating Properties.
J Exp Pharmacol. 2020 Aug 25;12:285-300. doi: 10.2147/JEP.S256586. eCollection 2020.
- PubMed ID
- 32943948 [ View in PubMed]
- Abstract
BACKGROUND: Viloxazine was historically described as a norepinephrine reuptake inhibitor (NRI). Since NRIs have previously demonstrated efficacy in attention deficit/hyperactivity disorder (ADHD), viloxazine underwent contemporary investigation in the treatment of ADHD. Its clinical and safety profile, however, was found to be distinct from other ADHD medications targeting norepinephrine reuptake. Considering the complexity of neuropsychiatric disorders, understanding the mechanism of action (MoA) is an important differentiating point between viloxazine and other ADHD medications and provides pharmacology-based rationale for physicians prescribing appropriate therapy. METHODS: Viloxazine was evaluated in a series of in vitro binding and functional assays. Its effect on neurotransmitter levels in the brain was evaluated using microdialysis in freely moving rats. RESULTS: We report the effects of viloxazine on serotoninergic (5-HT) system. In vitro, viloxazine demonstrated antagonistic activity at 5-HT2B and agonistic activity at 5-HT2C receptors, along with predicted high receptor occupancy at clinical doses. In vivo, viloxazine increased extracellular 5-HT levels in the prefrontal cortex (PFC), a brain area implicated in ADHD. Viloxazine also exhibited moderate inhibitory effects on the norepinephrine transporter (NET) in vitro and in vivo, and elicited moderate activity at noradrenergic and dopaminergic systems. CONCLUSION: Viloxazine's ability to increase 5-HT levels in the PFC and its agonistic and antagonistic effects on certain 5-HT receptor subtypes, which were previously shown to suppress hyperlocomotion in animals, indicate that 5-HT modulating activity of viloxazine is an important (if not the predominant) component of its MoA, complemented by moderate NET inhibition. Supported by clinical data, these findings suggest the updated psychopharmacological profile of viloxazine can be best explained by its action as a serotonin norepinephrine modulating agent (SNMA).
DrugBank Data that Cites this Article
- Drugs
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Viloxazine 5-hydroxytryptamine receptor 2B Protein Humans YesAntagonistDetails Viloxazine 5-hydroxytryptamine receptor 2C Protein Humans YesAgonistDetails Viloxazine Histamine H1 receptor Protein Humans UnknownAntagonistDetails Viloxazine Histamine H2 receptor Protein Humans UnknownAntagonistDetails Viloxazine Muscarinic acetylcholine receptor M1 Protein Humans UnknownAntagonistDetails Viloxazine Muscarinic acetylcholine receptor M2 Protein Humans UnknownAntagonistDetails Viloxazine Muscarinic acetylcholine receptor M3 Protein Humans UnknownAntagonistDetails Viloxazine Muscarinic acetylcholine receptor M4 Protein Humans UnknownAntagonistDetails Viloxazine Sodium-dependent noradrenaline transporter Protein Humans YesInhibitorDetails