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Sedative and Hypnotic Drugs
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Arup Kumar Misra, Pramod Kumar Sharma
Zolpidem, eszopiclone, and zaleplon are collectively known as “Z-drugs” though they have the same mechanism of action as benzodiazepines but they are structurally unrelated (Gregory, 2016). Ramelteon and tasimelteon are the melatonin receptor agonists which are approved by US FDA as newer hypnotics indicated for non-24-h sleep–wake disorders (Laudon, 2014). An orexin receptor antagonist, suvorexant was introduced in the market in August 2014 and is indicated to improve sleep duration. Buspirone is a slow-onset anxiolytic agent differing from the conventional sedative–hypnotics in their mechanism of action (Mendelson, 1990).
The metabolism of the dual orexin receptor antagonist daridorexant
Published in Xenobiotica, 2023
Alexander Treiber, Stephane Delahaye, Aude Weigel, Päivi Aeänismaa, John Gatfield, Swen Seeland
The work presented herein was performed as part of the preclinical safety assessment of the dual orexin receptor antagonist daridorexant, developed for the treatment of insomnia disorder. The orexin system consists of two G protein-coupled receptors, OX1 and OX2, and two ligand proteins called orexin A and orexin B. Binding of these ligands to OX1 and OX2 controls the awake state during the day, and an overactive orexin system manifests as difficulties in falling and staying asleep. From a drug discovery perspective, the major challenges for a sleep drug are the tailoring of sleep onset and sleep duration in order to minimise the time spent awake in bed, to maintain the sleep effect throughout the entire night and to avoid next-morning residual effects. Physiology-based pharmacokinetic modelling has been used to select daridorexant out of a group of structurally related compounds with proven potency on both target proteins, brain penetration ability and robust effects in animal models of sleep (Treiber et al. 2017; Boss et al. 2020).
Migraine and obesity: what is the real direction of their association?
Published in Expert Review of Neurotherapeutics, 2023
Soodeh Razeghi Jahromi, Fahimeh Martami, Kasra Morad Soltani, Mansoureh Togha
Orexin has been reported to modulate the desire to feed by acting through OXR1 and OXR2 receptors [20]. Central administration of orexin in rats was found to increase food intake [59]. Preclinical and clinical studies also support the role of orexins in pain development [60,61]. In rat pain models, intrathecal administration of OXA showed an anti-hyperalgesic effect [62]. The specificity of the anti-hyperalgesic role of OXA is reflected through its inhibition when pretreated with the orexin receptor antagonist [63]. Moreover, in a human study, an elevated level of OXA was observed in the cerebrospinal fluid of patients with chronic daily headache [64]. Evidence showing an anti-hyperalgesic effect for OXA in animal experiments and increased cerebrospinal fluid levels of OXA among patients with chronic daily headache raises the hypothesis that there may be orexin resistance or receptor dysfunction in chronic headache sufferers.
Clinical drug development for dementia with Lewy bodies: past and present
Published in Expert Opinion on Investigational Drugs, 2019
Garam Lee, Jeffrey Cummings, Boris Decourt, James B. Leverenz, Marwan N. Sabbagh
Modafinil and armodafinil are wake-promoting agents approved for excessive sleepiness associated with narcolepsy and shift work sleep disorder. They have been shown to increase dopamine in the brain by blocking dopamine transporters; however their precise MOA related to sleep/wake regulation is unknown [81]. Interestingly, they are considered to have limited interaction with dopamine receptors, and thus are of interest for excessive daytime somnolence in DLB [81]. An open-label pilot study (NCT01023672) of armodafinil in DLB showed improvements in hypersomnia and wakefulness with reasonable tolerability and no worsening of parkinsonism [81]. Modafinil did not show improvement and exacerbated psychotic symptoms in a small case study [82]. A recent Phase 3 trial of suvorexant showed a benefit in AD patients with insomnia [83]; trials of the dual orexin receptor antagonist class are warranted in DLB [84].