Yu Chungping, Garcia-Olivares Jennie, Candler Shawn, Schwabe Stefan, Maletic Vladimir
Supernus Pharmaceuticals, Inc., Rockville, MD, USA.
Department of Psychiatry/Behavioral Science, University of South Carolina School of Medicine, Greenville, SC, USA.
J Exp Pharmacol. 2020 Aug 25;12:285-300. doi: 10.2147/JEP.S256586. eCollection 2020.
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 and agonistic activity at 5-HT 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.
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).
维洛沙嗪在历史上被描述为一种去甲肾上腺素再摄取抑制剂（NRI）。由于NRI此前已在注意力缺陷多动障碍（ADHD）中显示出疗效，维洛沙嗪因此接受了ADHD治疗方面的当代研究。然而，发现其临床和安全性特征与其他针对去甲肾上腺素再摄取的ADHD药物不同。考虑到神经精神疾病的复杂性，了解作用机制（MoA）是维洛沙嗪与其他ADHD药物之间的一个重要区别点，并为医生开具适当治疗方案提供基于药理学的理论依据。
在一系列体外结合和功能试验中对维洛沙嗪进行了评估。使用微透析技术在自由活动的大鼠中评估其对大脑神经递质水平的影响。
我们报告了维洛沙嗪对5-羟色胺能（5-HT）系统的影响。在体外，维洛沙嗪在5-HT受体上表现出拮抗活性，在5-HT受体上表现出激动活性，并且在临床剂量下预测具有较高的受体占有率。在体内，维洛沙嗪增加了前额叶皮质（PFC）中的细胞外5-HT水平，PFC是一个与ADHD有关的脑区。维洛沙嗪在体外和体内对去甲肾上腺素转运体（NET）也表现出中度抑制作用，并在去甲肾上腺素能和多巴胺能系统中引发中度活性。
维洛沙嗪增加PFC中5-HT水平的能力及其对某些5-HT受体亚型的激动和拮抗作用，此前已证明这些作用可抑制动物的过度活动，这表明维洛沙嗪的5-HT调节活性是其MoA的一个重要（如果不是主要的）组成部分，并辅以中度的NET抑制作用。在临床数据的支持下，这些发现表明，维洛沙嗪作为一种5-羟色胺去甲肾上腺素调节剂（SNMA）的作用，能够最好地解释其更新后的精神药理学特征。
