Yu Chungping, Gopalakrishnan Gopakumar
Preclinical DMPK and Pharmacology, Supernus Pharmaceuticals, Inc., Rockville, MD, USA,
Preclinical Toxicology, Supernus Pharmaceuticals, Inc., Rockville, MD, USA.
J Exp Pharmacol. 2018 Nov 21;10:65-73. doi: 10.2147/JEP.S180777. eCollection 2018.
Impulsive aggression (IA) is considered a maladaptive form of aggression that is reactive and overt and occurs outside of the acceptable social context. Many children and adolescents with attention-deficit/hyperactivity disorder (ADHD) display clinically significant aggression, with the predominant subtype being IA. However, there is currently no Food and Drug Administration-approved medication specifically to treat IA. The pathophysiology of IA is not fully understood, although it has been suggested to include the dopamine, norepinephrine, and serotonin systems.
SPN-810 (extended-release molindone) is being developed for the novel indication of IA and is currently being studied in patients treated for ADHD. Molindone is an indole derivative and a dopamine D receptor antagonist.
The in vitro pharmacological studies described in the current manuscript demonstrate that the active substance molindone (SPN-810M) is a potent antagonist for the dopamine receptors, D and D, and the serotonin receptor, 5-HT, at therapeutic concentrations. The in vitro studies further demonstrate that the antagonist effect of SPN-810M is due to the parent drug and not the metabolites, and that the antagonism is not affected by the presence of norepinephrine or dopamine neurotransmitters. In addition, studies investigating the potential differential effects of the enantiomers of SPN-810M have demonstrated that the R(-) enantiomer is more potent than S(+), showing greater regulatory effect on D and D receptors.
Overall, the results of the in vitro SPN-810M pharmacological studies provide some insight into how SPN-810M modulates the serotonin and dopamine pathways that play a role in IA.
冲动性攻击行为（IA）被认为是一种适应不良的攻击形式，具有反应性和公开性，且发生在可接受的社会背景之外。许多患有注意力缺陷/多动障碍（ADHD）的儿童和青少年表现出具有临床意义的攻击行为，其中主要亚型为IA。然而，目前尚无美国食品药品监督管理局批准的专门用于治疗IA的药物。尽管有人提出IA的病理生理学包括多巴胺、去甲肾上腺素和5-羟色胺系统，但其尚未完全明确。
SPN-810（缓释吗茚酮）正被开发用于IA这一新适应症，目前正在接受ADHD治疗的患者中进行研究。吗茚酮是一种吲哚衍生物，也是一种多巴胺D受体拮抗剂。
当前稿件中描述的体外药理学研究表明，活性物质吗茚酮（SPN-810M）在治疗浓度下是多巴胺受体D1和D2以及5-羟色胺受体5-HT2A的强效拮抗剂。体外研究进一步表明，SPN-810M的拮抗作用归因于母体药物而非代谢产物，且这种拮抗作用不受去甲肾上腺素或多巴胺神经递质存在的影响。此外，对SPN-810M对映体潜在差异效应的研究表明，R(-)对映体比S(+)对映体更具效力，对D1和D受体显示出更大的调节作用。
总体而言，体外SPN-810M药理学研究结果为SPN-810M如何调节在IA中起作用的5-羟色胺和多巴胺途径提供了一些见解。
