Lauflumide (NLS-4) Is a New Potent Wake-Promoting Compound

Gianina Luca,Bruno Figadère,Mojtaba Bandarabadi,Laurent Ferrié,Eric Konofal,Michel Lecendreux,Mehdi Tafti

doi:10.3389/fnins.2018.00519

Abstract

Psychostimulants are used for the treatment of excessive daytime sleepiness in a wide range of sleep disorders as well as in attention deficit hyperactivity disorder or cognitive impairment in neuropsychiatric disorders. Here, we tested in mice the wake-promoting properties of NLS-4 and its effects on the following sleep as compared with those of modafinil and vehicle. C57BL/6J mice were intraperitoneally injected with vehicle, NLS-4 (64 mg/kg), or modafinil (150 mg/kg) at light onset. EEG and EMG were recorded continuously for 24 h after injections and vigilance states as well as EEG power densities were analyzed. NLS-4 at 64 mg/kg induced significantly longer wakefulness duration than modafinil at 150 mg/kg. Although no significant sleep rebound was observed after sleep onset for both treatments as compared with their vehicles, modafinil-treated mice showed significantly more NREM sleep when compared to NLS-4. Spectral analysis of the NREM EEG after NLS-4 treatment indicated an increased power density in delta activity (0.75–3.5 Hz) and a decreased power in theta frequency range (6.25–7.25 Hz), while there was no differences after modafinil treatment. Also, time course analysis of the delta activity showed a significant increase only during the first 2 time intervals of sleep after NLS-4 treatment, while delta power was increased during the first 9 time intervals after modafinil. Our results indicate that NLS-4 is a highly potent wake-promoting drug with no sign of hypersomnia rebound. As opposed to modafinil, recovery sleep after NLS-4 treatment is characterized by less NREM amount and delta activity, suggesting a lower need for recovery despite longer drug-induced wakefulness.

Highlights

Excessive daytime sleepiness (EDS) is a major symptom of a wide range of sleep disorders
Preliminary findings suggest that NLS-4 is a selective dopamine reuptake inhibitor, blocking (83%) dopamine transporter (DAT), higher than methylphenidate and without deleterious effects on peripheral adrenergic systems involved in hypertension (Study 100014859 CEREP 20/03/14, unpublished data)
All statistical analyses were performed with GraphPad Prism and all post-hoc tests were Sidak corrected for multiple comparisons. Both NLS-4 (N = 8) and modafinil (N = 8) increased the duration of drug-induced wakefulness compared with vehicle (Figure 1C)

Summary

Introduction

Excessive daytime sleepiness (EDS) is a major symptom of a wide range of sleep disorders. Pitolisant, a histamine H3 inverse agonist is the newest and approved second-generation stimulant with efficacy comparable to modafinil (Dauvilliers et al, 2013). Another second-generation wake-promoting drug, JZP-110 is in advanced clinical trials for the treatment of EDS in narcolepsy and sleep apnea (Bogan et al, 2015; Ruoff et al, 2016). This bis (p-fluoro) ring-substituted derivative of modafinil (Figure 1A) is an original potent wake-promoting agent and produces anti-aggressive effects in rats, which modafinil does not (Patent No.:US9,637.447B2). Preliminary findings suggest that NLS-4 is a selective dopamine reuptake inhibitor, blocking (83%) dopamine transporter (DAT), higher than methylphenidate and without deleterious effects on peripheral adrenergic systems involved in hypertension (Study 100014859 CEREP 20/03/14, unpublished data)

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