In Vitro and In Silico Characterization of Lemborexant (E2006), a Novel Dual Orexin Receptor Antagonist.

نویسندگان

  • Carsten Theodor Beuckmann
  • Michiyuki Suzuki
  • Takashi Ueno
  • Kazuya Nagaoka
  • Tohru Arai
  • Hiroyuki Higashiyama
چکیده

Orexin (hypocretin) neuropeptides have, among others, been implicated in arousal/sleep control, and antagonizing the orexin signaling pathway has been previously demonstrated to promote sleep in animals and humans. This mechanism opens up a new therapeutic approach to curb excessive wakefulness in insomnia disorder rather than to promote sleep-related signaling. Here we describe the preclinical pharmacological in vitro and in silico characterization of lemborexant ((1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide)), a dual orexin receptor antagonist (DORA), as a novel experimental therapeutic agent for the symptomatic treatment of insomnia disorder and compare its properties to two other DORAs, almorexant and suvorexant. Lemborexant binds to both orexin receptors and functionally inhibits them in a competitive manner with low nanomolar potency, without any species difference apparent among human, rat, and mouse receptors. Binding and dissociation kinetics on both orexin receptors are rapid. Lemborexant is selective for both orexin receptors over 88 other receptors, transporters, and ion channels of important physiologic function. In silico modeling of lemborexant into the orexin receptors showed that it assumes the same type of conformation within the receptor-binding pocket as suvorexant, the π-stacked horseshoe-like conformation.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Suvorexant, a dual orexin receptor antagonist, protected seizure through interaction with GABAA and glutamate receptors

Orexin can increase neuronal excitability and induce epileptic activity. In this study, the effects of suvorexant (orexin receptor antagonist) on pentylenetetrazol (PTZ) and maximal electroshock (MES)-induced seizure were investigated. Mice were divided into 5 groups of six animals each including normal saline (10 ml/kg), diazepam (2 mg/kg) and suvorexant (50, 100 and 200 mg/kg) groups. In PTZ ...

متن کامل

Suvorexant, a dual orexin receptor antagonist, protected seizure through interaction with GABAA and glutamate receptors

Orexin can increase neuronal excitability and induce epileptic activity. In this study, the effects of suvorexant (orexin receptor antagonist) on pentylenetetrazol (PTZ) and maximal electroshock (MES)-induced seizure were investigated. Mice were divided into 5 groups of six animals each including normal saline (10 ml/kg), diazepam (2 mg/kg) and suvorexant (50, 100 and 200 mg/kg) groups. In PTZ ...

متن کامل

Administration of orexin receptor 1 antagonist into the rostral ventromedial medulla increased swim stress-induced antinociception in rat

Objective(s): Intracerebroventricular injection of orexin-A (hypocretin-1) antagonist has been shown to inhibit stress-induced analgesia. However the locations of central sites that may mediate these effects have not been totally demonstrated. This study was performed to investigate the role of rostral ventromedial medulla (RVM) orexin receptor 1 in stress-induced analgesia (SIA). Materials and...

متن کامل

Assesment of orexin receptor 1 in stress attenuated nociceptive behaviours in formalin test

Introduction: It is known that acute and chronic stress induce hormonal and neuronal changes which affecting both pain threshold and nociceptive behaviours. Orexin plays an important role in modulation of pain and stress. Considering pain modulation during stress and the role of orexin in pain and stress, orexin might be involved in pain modulation during stress.We evaluated the involvement ...

متن کامل

Molecular docking and in silico ADME prediction of Ticagrelor as an antagonist of the P2Y12 receptor

The purpose of the present research work is prediction of electronic and physico-chemical properties of the novel medicinal compound Ticagrelor (AZD6140) using density functional theory (DFT) method. Firstly, its molecular structure was optimized at B3LYP/6-311++G(d,p) basis set of theory at room temperature. The global reactivity indices used to study the reactivity and stability of the title ...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • The Journal of pharmacology and experimental therapeutics

دوره 362 2  شماره 

صفحات  -

تاریخ انتشار 2017