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New Insights Into the Mechanism of Action of Viloxazine: Serotonin and Norepinephrine Modulating Properties

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New Insights Into the Mechanism of Action of Viloxazine: Serotonin and Norepinephrine Modulating Properties Journal of Experimental Pharmacology Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH New Insights into the Mechanism of Action of Viloxazine: Serotonin and Norepinephrine Modulating Properties This article was published in the following Dove Press journal: Journal of Experimental Pharmacology Chungping Yu1 Background: Viloxazine was historically described as a norepinephrine reuptake inhibitor Jennie Garcia-Olivares1 (NRI). Since NRIs have previously demonstrated efficacy in attention deficit/hyperactivity Shawn Candler1 disorder (ADHD), viloxazine underwent contemporary investigation in the treatment of Stefan Schwabe1 ADHD. Its clinical and safety profile, however, was found to be distinct from other Vladimir Maletic2 ADHD medications targeting norepinephrine reuptake. Considering the complexity of neu­ ropsychiatric disorders, understanding the mechanism of action (MoA) is an important 1 Supernus Pharmaceuticals, Inc., differentiating point between viloxazine and other ADHD medications and provides phar­ Rockville, MD, USA; 2Department of Psychiatry/Behavioral Science, University macology-based rationale for physicians prescribing appropriate therapy. of South Carolina School of Medicine, Methods: Viloxazine was evaluated in a series of in vitro binding and functional assays. Its Greenville, SC, USA 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 trans­ porter (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 psychophar­ macological profile of viloxazine can be best explained by its action as a serotonin norepi­ nephrine modulating agent (SNMA). Keywords: viloxazine, ADHD, serotonin norepinephrine modulating agent, norepinephrine transporter, mechanism of action, SPN-812 Introduction Viloxazine was firstapproved in the 1970s in the United Kingdom and in several other European countries for the treatment of depression in adults, spurring a series of mechanistic studies into the compound during the 1970s and 1980s.1,2 During these Correspondence: Chungping Yu Supernus Pharmaceuticals, Inc., 9715 Key decades, viloxazine was characterized as a norepinephrine (NE) reuptake inhibitor West Avenue, Rockville, MD 20850, USA (NRI), which was supported by its similarity to the tricyclic antidepressants in its Tel +1 301 838 2679 3–5 Email [email protected] ability to potentiate noradrenergic effects across multiple animal models. submit your manuscript | www.dovepress.com Journal of Experimental Pharmacology 2020:12 285–300 285 DovePress © 2020 Yu et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php http://doi.org/10.2147/JEP.S256586 and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Yu et al Dovepress Based on the original mechanism of action (MoA) and Table 1 Monoamine Uptake Inhibition, Transporter Binding the established therapeutic benefit of targeting NE neuro­ Affinity, and Selectivity for Viloxazine, Atomoxetine, and transmission in the treatment of attention-deficit/hyperac­ Reboxetine. tivity disorder (ADHD), an extended-release formulation Viloxazine Atomoxetine Reboxetine of this molecule, SPN-812 (viloxazine extended-release), [3H]-NE uptake 2300a 3.4b 8.2c is currently being developed for the treatment of ADHD in [3H]-5-HT uptake >10,000a 390b 1070c children, adolescents, and adults.6–9 In a proof-of-concept [3H]-DA uptake NCa 1750b NCc d d e e f study and recently completed Phase 3 trials,6–8 SPN-812 NET binding 155 2 –5 1.1 –11 SERT binding 17,300d 9d–77e 129e–440f was effective in reducing symptoms of hyperactivity, DAT binding >100,000d 1080d–1451e >10,000f impulsivity, and inattention in children and adolescents KD (SERT)/KD (NET) 111 4 10 with ADHD. Treatment with SPN-812 exhibited Ki (SERT)/Ki (NET) 15 40–117 −9 a a safety profile somewhat different from that of commonly Notes: All values in 10 M. Ki calculated from rat hypothalamic synaptosomes uptake b c assay. Ki calculated from rat cerebral cortex synaptosomes uptake assay. Ki calculated prescribed NRI antidepressants and ADHD pharma­ d from rat striatal synaptosomes uptake assay. KD calculated from competition assays cotherapies with potent NRI activity. Specifically, in con­ using [3H]-nisoxetine for hNET, [3H]-imipramine for hSERT, and [3H]-WIN35428 for e 3 3 hDAT. Ki calculated using specific radiolabeled ligands, [ H]-nisoxetine for NET, [ H]- trast to potent noradrenergic agents, SPN-812 3 f paroxetine for SERT, and [ H]-WIN35428 for DAT. Ki calculated using specific radiola­ demonstrated a low incidence of cardiac-related adverse beled ligands, [3H]-nisoxetine for NE, [3H]-citalopram for 5-HT, and [3H]-WIN35428 for 15–18 events.10−14 The low incidence of cardiovascular events DA uptake sites. Data from these studies. Abbreviations: 5-HT, serotonin; DA, dopamine; DAT, dopamine transporter; KD, (such as increased blood pressure or heart rate) associated dissociation constant; Ki, inhibition constant; NC, not calculated; NE, norepinephr­ ine; NET, norepinephrine transporter; SERT, serotonin transporter. with viloxazine—both historically and in these contempor­ ary investigations—suggests that viloxazine possesses only moderate noradrenergic activity.2,10,12 Distinct clinical profile of viloxazine compared to In addition to its clinical profile, historical in vitro NRIs observed in recent ADHD clinical trials, along pharmacology data indicate that the inhibitory potency of with limited in vitro and animal data emerging from viloxazine for NE and 5-HT uptake is different from that previous studies, led us to hypothesize a more complex of other known NRIs, such as atomoxetine and reboxetine. MoA of viloxazine than was previously suggested. Previous data have demonstrated that viloxazine exhibits A series of pharmacological studies using current tech­ a more moderate inhibitory effect on NE uptake, with an niques and methodologies were conducted in order to inhibitory constant (Ki) of 2300 nM, compared to the Ki of further elucidate the activity of viloxazine in neuro­ 3.4 and 8.2 nM for atomoxetine and reboxetine, respec­ transmitter systems, including comprehensive radioli­ tively (Table 1).15–18 Viloxazine is almost devoid of any gand binding affinity assays and in vitro cellular 5-HT uptake inhibitory activity (Ki > 10,000 nM), while functional activity assays at key monoamine transpor­ atomoxetine and reboxetine have a moderate potency for ters and receptors, and a brain microdialysis study. The 5-HT uptake inhibition (Ki = 390 and 1070 nM, respec­ microdialysis study focused on the prefrontal cortex tively). Likewise, viloxazine has consistently demon­ (PFC), nucleus accumbens (Acb), and amygdala strated a relatively low affinity towards the NE (Amg). The PFC is an established area associated transporter (NET) in in vitro binding competition assays. with ADHD pathophysiology, involving the regulation Still, viloxazine exhibits higher selectivity towards NET of attention, behavior, and emotions through extensive over the 5-HT transporter (SERT) (dissociation constant projections to multiple regions including Acb and KD ratio = 110) and almost negligible affinity for the Amg, which also play a key role in substance use 20,21 dopamine (DA) transporter (DAT) (KD > 100,000 nM; disorders. To better understand the role of viloxa­ Table 1). zine in modulating neurotransmitter systems involved Furthermore, several in vitro and in vivo observations in ADHD and its potential risk of misuse, the neuro­ from previous studies have indicated that viloxazine might transmitter levels in all three brain regions were enhance 5-HT neurotransmission.19 Evidence also sug­ investigated. gests that viloxazine lacks the characteristic neurochemical These studies will help improve current understanding properties of the amphetamines or monoamine oxidase of the MoA of viloxazine providing a better pharmacol­ inhibitors, and is absent of inhibitory activity towards ogy-based rationale to treat patients with ADHD and pos­ peripheral acetylcholine (ACh) or histamine (His).2,3 sibly other neuropsychiatric disorders. 286 submit your
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