Lorediplon: A new GABAA modulator drug for treatment of insomnia

Abstract

Drugs acting on the GABAA receptor such as the so-called Z-drugs Zolpidem, Zaleplon, and Eszopiclone are widely used in the treatment of insomnia. Despite their efficacy and good safety profile however, none of these drugs represent the perfect solution to the treatment of this disorder. Therefore, there is still room for improvement of this class of drugs and for addressing still unmet clinical needs. Lorediplon is a new promising drug acting on the GABAA receptor currently under clinical evaluation which selectively binds to the α1 subunit of the GABAA receptor. In animals, Lorediplon showed potent sedative effects and much less potent activity on inhibition of muscular tone. No development of tolerance was shown to the sedative effect of Lorediplon after 5 days continuous daily treatment. Preclinical in vivo studies also demonstrated that Lorediplon at hypnotic dose has a low risk of development of amnesia, next-day hangover effects, or development of physical dependence. The pharmacological activity and pharmacokinetic profile of Lorediplon were evaluated in three clinical studies. After oral administration, the molecule is absorbed quickly with a dose-related linear profile and Tmax around 2 h. In a phase advance model of insomnia in healthy human volunteers, Lorediplon, compared to Zolpidem, showed a longer lasting maintenance of sleep. The sleep induced by Lorediplon was rated by the subjects participating in the study as of improved quality while EEG recording in mice demonstrated that Lorediploninduced sleep is less fragmented and more physiological than that induced by Zolpidem. Lorediplon also shows an excellent safety profile with a comparable to Zolpidem number of adverse events reported in clinical studies. Therefore, Lorediplon has the potential to become the best-in-class GABAA acting hypnotic and a major player in the treatment of insomnia and related disorders.