New Insights into the Mechanism of Action of Viloxazine: Serotonin and Norepinephrine Modulating Properties.
ADHD
SPN-812
mechanism of action
norepinephrine transporter
serotonin norepinephrine modulating agent
viloxazine
Journal
Journal of experimental pharmacology
ISSN: 1179-1454
Titre abrégé: J Exp Pharmacol
Pays: New Zealand
ID NLM: 101530345
Informations de publication
Date de publication:
2020
2020
Historique:
received:
04
04
2020
accepted:
25
07
2020
entrez:
18
9
2020
pubmed:
19
9
2020
medline:
19
9
2020
Statut:
epublish
Résumé
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. 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. We report the effects of viloxazine on serotoninergic (5-HT) system. In vitro, viloxazine demonstrated antagonistic activity at 5-HT 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).
Sections du résumé
BACKGROUND
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
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
RESULTS
We report the effects of viloxazine on serotoninergic (5-HT) system. In vitro, viloxazine demonstrated antagonistic activity at 5-HT
CONCLUSION
CONCLUSIONS
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).
Identifiants
pubmed: 32943948
doi: 10.2147/JEP.S256586
pii: 256586
pmc: PMC7473988
doi:
Types de publication
Journal Article
Langues
eng
Pagination
285-300Informations de copyright
© 2020 Yu et al.
Déclaration de conflit d'intérêts
CY, JGO, SC, and SS are employees of Supernus Pharmaceuticals, Inc. VM is an employee of the University of South Carolina School of Medicine. He is a consultant for ACADIA Pharmaceuticals Inc.; Alfasigma USA, Inc.; Alkermes, Inc.; Allergan; Eisai-Purdue; Intra-Cellular Therapies; Janssen; H. Lundbeck A/S; Otsuka America Pharmaceutical, Inc.; Sage Pharmaceuticals; Sunovion Pharmaceuticals Inc.; Supernus Pharmaceuticals, Inc.; and Takeda Pharmaceutical Company Limited. He serves on the speakers bureau of ACADIA Pharmaceuticals Inc.; Alkermes, Inc.; Allergan; Ironshore; Intra-Cellular; Janssen; H. Lundbeck A/S; Otsuka America Pharmaceutical, Inc.; Sunovion Pharmaceuticals Inc.; and Takeda Pharmaceutical Company Limited. The authors report no other conflicts of interest in this work.
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