Rationale

Samelisant (SUVN-G3031) is a potent and selective histamine H3 receptor (H3R) inverse agonist with good brain penetration and oral bioavailability.

Objectives

Pharmacological and neurochemical characterisation to support the utility of Samelisant (SUVN-G3031) in the treatment of sleep-related disorders like narcolepsy.

Methods

Samelisant (SUVN-G3031) was tested in rat brain microdialysis studies for evaluation of modulation in histamine, dopamine and norepinephrine. Sleep EEG studies were carried out in orexin knockout mice to study the effects of Samelisant (SUVN-G3031) on the sleep–wake cycle and cataplexy.

Results

Samelisant (SUVN-G3031) has a similar binding affinity towards human (hH3R; K_i = 8.7 nM) and rat (rH3R; K_i = 9.8 nM) H3R indicating no inter-species differences. Samelisant (SUVN-G3031) displays inverse agonist activity and it exhibits very high selectivity towards H3R. Samelisant (SUVN-G3031) treatment in mice produced a dose-dependent increase in tele-methylhistamine levels indicating the activation of histaminergic neurotransmission. Apart from increasing the levels of histamine, Samelisant (SUVN-G3031) also modulates dopamine and norepinephrine levels in the cerebral cortex while it has no effects on dopamine levels in the striatum or nucleus accumbens. Treatment with Samelisant (SUVN-G3031; 10 and 30 mg/kg, p.o.) produced a significant increase in wakefulness with a concomitant decrease in NREM sleep in orexin knockout mice subjected to sleep EEG. Samelisant (SUVN-G3031) also produced a significant decrease in Direct REM sleep onset (DREM) episodes, demonstrating its anticataplectic effects in an animal model relevant to narcolepsy. Modulation in cortical levels of histamine, norepinephrine and dopamine provides the neurochemical basis for wake-promoting and anticataplectic effects observed in orexin knockout mice.

Conclusions

Pre-clinical studies of Samelisant (SUVN-G3031) provide a strong support for utility in the treatment of sleep-related disorders related to EDS and is currently being evaluated in a phase 2 proof of concept study in the USA for the treatment of narcolepsy with and without cataplexy.

中文翻译：

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Samelisant（SUVN-G3031），一种有效，选择性和口服的组胺H3受体反向激动剂，可用于发作性睡病的潜在治疗：药理和神经化学表征

基本原理

Samelisant（SUVN-G3031）是一种有效的选择性组胺H3受体（H3R）反向激动剂，具有良好的脑渗透性和口服生物利用度。

目标

药理和神经化学特性可支持Samelisant（SUVN-G3031）在治疗与睡眠相关的疾病（如发作性睡病）中的用途。

方法

在大鼠脑微透析研究中对Samelisant（SUVN-G3031）进行了测试，以评估组胺，多巴胺和去甲肾上腺素的调节作用。在orexin基因敲除小鼠中进行了睡眠EEG研究，以研究Samelisant（SUVN-G3031）对睡眠-觉醒周期和瘫痪的影响。

结果

Samelisant（SUVN-G3031）对人（hH3R; K _i = 8.7 nM）和大鼠（rH3R; K _i = 9.8 nM）H3R具有相似的结合亲和力，表明种间无差异。Samelisant（SUVN-G3031）显示出反向激动剂活性，并且对H3R的选择性很高。小鼠中的Samelisant（SUVN-G3031）治疗可产生剂量依赖性的遥视增加-甲基组胺水平表明组胺能神经传递的激活。除了增加组胺水平外，Samelisant（SUVN-G3031）还调节大脑皮层中的多巴胺和去甲肾上腺素水平，而对纹状体或伏隔核中的多巴胺水平没有影响。用Samelisant（SUVN-G3031; 10和30 mg / kg，口服）治疗可显着提高清醒率，同时使接受睡眠脑电图的orexin基因敲除小鼠的NREM睡眠减少。Samelisant（SUVN-G3031）在直接REM睡眠发作（DREM）发作中也产生了显着降低，证明了它在与发作性睡病相关的动物模型中具有抗分解代谢作用。皮质中组胺水平的调节

结论

Samelisant（SUVN-G3031）的临床前研究为治疗与EDS相关的睡眠相关疾病提供了有力的支持，并且目前正在美国进行的第二阶段概念验证研究中进行评估，以治疗嗜睡性睡病。而且没有白痴。