filorexant (MK6096) / Merck (MSD) - LARVOL DELTA

Agonists for glutamate, acetylcholine, and orexin cause non-photic phase shifts when applied to the intergeniculate leaflet. (PubMed, Neuroscience) - "Pretreatment with the dual OX1/OX2 receptor antagonist MK-6096 did not attenuate phase shifts to 3 h midday SD. While a cocktail of both carbachol and NMDA inhibited each other's phase shifting effects, a cocktail that included orexin, carbachol and NMDA reversed this inhibition and yielded the largest phase shifts of all. This suggests that the IGL is likely activated by numerous convergent arousal inputs during a phase-shifting non-photic manipulation."

Journal

Efficacy of orexin antagonists for the management of major depressive disorder: A systematic review of randomized clinical trials. (PubMed, J Affect Disord) - "However, filorexant did not exhibit a significant difference in MADRS total scores compared to placebo. Taken together, the potential of orexin receptor antagonists, particularly seltorexant, as a novel avenue for managing depressive symptoms in MDD. Further research is warranted to better understand their role in depression treatment and safety profile."

Clinical • Journal • Review • CNS Disorders • Depression • Insomnia • Major Depressive Disorder • Mood Disorders • Psychiatry • Sleep Disorder

Orexin Receptor Antagonists as Adjunct Drugs for the Treatment of Depression: A Mini Meta-Analysis. (PubMed, Noro Psikiyatr Ars) - "Search words were (depression OR mood disorder OR affective disorder) AND (orexin OR orx OR hypocretin OR orx1 OR orx2 OR orexin receptor antagonist OR almorexant OR suvorexant OR lemborexant OR daridorexant OR seltorexant OR vornorexant OR filorexant). Considering the physiological effects of orexin on behaviors, ORAs may be promising new treatment modalities in the treatment of many psychiatric disorders other than insomnia. However, these results are preliminary and further studies with different ORAs at different doses and with different samples are needed."

Journal • Retrospective data • Review • CNS Disorders • Depression • Insomnia • Mental Retardation • Mood Disorders • Psychiatry • Sleep Disorder

Dual orexin/hypocretin receptor antagonism attenuates NMDA receptor hypofunction-induced attentional impairments in a rat model of schizophrenia. (PubMed, Behav Brain Res) - "Dizocilpine-induced increases in signal trial deficits, correct response latencies, and errors of omission were reduced following infusions of the 0.1mM, but not 1mM, dose of filorexant. As such, orexin receptor blockade may improve attentional deficits in a state of NMDA receptor hypofunction."

Journal • Preclinical • CNS Disorders • Psychiatry • Schizophrenia

Orexin Receptor Antagonists in the Treatment of Depression: A Leading Article Summarising Pre-clinical and Clinical Studies. (PubMed, CNS Drugs) - "To date, four published RCTs (one with the DORA filorexant and three with the selective orexin 2 receptor antagonist seltorexant), have compared an ORA with placebo in the treatment of MDD. Only one of these demonstrated a statistically significant difference relative to placebo."

Journal • Preclinical • CNS Disorders • Depression • Insomnia • Major Depressive Disorder • Mood Disorders • Psychiatry • Sleep Disorder

The effects of filorexant, a dual orexin receptor antagonist, on evoked prefrontal cortical and hippocampal gamma oscillations in a model of NMDA receptor hypofunction (Neuroscience 2022) - "When co-administered with 0.5 mg/kg of MK-801, none of the concentrations of filorexant were able to normalize deficient gamma entrainment. In conclusion, dual orexin receptor antagonism may improve attentional behavioral outcomes in an NMDA receptor hypofunction model of schizophrenia through mechanisms not relevant to the restoration of evoked gamma activity in these attention-associated brain areas."

CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

One-Step Regio- and Stereoselective Electrochemical Synthesis of Orexin Receptor Antagonist Oxidative Metabolites. (PubMed, J Org Chem) - "The electrochemical oxidation of MK-8133 and MK-6096 was conducted in aqueous media and found to produce the corresponding α-piperidinols with exclusive regio- and stereoselectivity, as confirmed by high-resolution nuclear magnetic resonance (NMR) characterization of products. Based on density functional theory (DFT) calculations, the exceptional regio- and stereoselectivity for this electrochemical oxidation are governed by more favorable energetics of the transition state, leading to the preferred secondary carbon radical α to the amide group and subsequent steric hindrance associated with the U-shaped conformation of the cation derived from the secondary α-carbon radical, respectively."

Journal

Orexin Receptor Antagonists and Insomnia. (PubMed, Curr Psychiatry Rep) - "Research on suvorexant in recent years gradually focus on comorbid insomnia, while lemborexant and daridorexant were still being validated in primary insomnia...Although filorexant has also shown a certain sleep-promoting effect, there are few clinical or experimental studies on sleep-related aspects of filorexant in recent years. As for selective ORAs, orexin receptor 2 antagonist seltorexant still has not yet reached phase 3. High-quality clinical trials in insomnia populations are needed which directly compare authorized ORAs and investigate non-approved ORAs, the use of ORAs in comorbid insomnia, and the orexin signaling system pathophysiology in insomnia."

Journal • Review • CNS Disorders • Insomnia • Sleep Disorder

Orexin-1 receptor antagonism alleviates dizocilpine-induced attentional impairments in an NMDA receptor hypofunction model of schizophrenia (Neuroscience 2021) - "Unlike filorexant, SB-334867 did not lessen omissions following dizocilpine exposure, perhaps a reflection of the role of the orexin-1 receptor in satiety-linked motivation. Thus, we propose that the orexin-1 receptor is an important target for minimizing the attentional deficits associated with NMDA receptor antagonism.; Grant Support: R01AG050518"

CNS Disorders • Psychiatry • Schizophrenia

Emerging Targets for Migraine Treatment. (PubMed, Neurol India) - "Filorexant is the only dual orexin receptor antagonist, which was tested in humans with negative results. Further and ongoing studies will determine the utility of these new therapies with lasmiditan and melatonin having demonstrated efficacy for the treatment of migraine."

Journal • Review • CNS Disorders • Migraine • ADCYAP1

Randomized controlled trial of the orexin receptor antagonist filorexant for migraine prophylaxis (Cephalalgia) - P2, N=235; Sponsor: MSD; NCT01513291; "There was no statistically significant difference between treatments for change from baseline in mean monthly migraine days (filorexant = -1.7, placebo = -1.3, difference = -0.4 (95% CI: -1.3, 0.4)) or headache days (filorexant = -1.7, placebo = -1.2, difference = -0.5 (95% CI: -1.4, 0.4)). Filorexant was generally well tolerated but was associated with a higher proportion of patients who reported adverse events than placebo (47% vs 37%), particularly somnolence (13% vs 4%)."

P2 data • Migraine

An Update on Dual Orexin Receptor Antagonists and Their Potential Role in Insomnia Therapeutics. (PubMed, J Clin Sleep Med) - "DORAs offer an additional treatment option for insomnia. More clinical trials are needed to robustly evaluate their safety and effectiveness in several subclasses of individuals with insomnia. Given the published literature, head-to-head comparisons to existing treatment for insomnia are warranted."

Journal

Optical Probing of Orexin/Hypocretin Receptor Antagonists. (PubMed, Sleep) - "Treatment with dual OX1/2R antagonists (DORAs) DORA12 and MK6096, as well as selective OX2R antagonist MK1064 and Zolpidem, but not selective OX1R antagonist 1SORA1, significantly reduced the bout length of optogenetic stimulation-evoked wakefulness episode...Treatment with dual OX1/2R antagonists improved memory function despite optogenetic sleep fragmentation caused impaired memory function in a NOR test. Our results show DORAs and selective OX2R antagonists stabilize sleep and improve sleep-dependent cognitive processes even when challenged by optogenetic stimulation mimicking highly arousing stimuli."

Journal

Dual orexin receptor antagonism attenuates dizocilpine-induced attentional impairments in a rat model of acute psychosis (Neuroscience 2019) - "Additionally, dizocilpine-linked trial omissions were reduced following filorexant infusions. Based on these findings, drugs which dampen orexin receptor activity may restore attentional and motivational abilities for those with SZ, possibly by assuaging subcortical hyperactivity and normalizing cortical function."

Preclinical