{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T12:36:55Z","timestamp":1786451815600,"version":"build-2736575974"},"reference-count":101,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82473840"],"award-info":[{"award-number":["82473840"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82473840"],"award-info":[{"award-number":["82473840"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Key Natural Science Foundation of Jiangsu Higher Education Institutions","award":["20KJA350002"],"award-info":[{"award-number":["20KJA350002"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Insomnia is a common sleep disorder that significantly impairs quality of life and increases the risk of various chronic diseases. Although conventional sedative\u2013hypnotic agents are effective, their clinical use is limited by tolerance, dependence, and residual next-day effects. The orexin system plays a critical role in sleep\u2013wake regulation through orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R), with OX2R serving as the primary mediator of wakefulness. Based on this mechanism, orexin receptor antagonists (ORAs) have been developed to promote sleep by suppressing wake-promoting signaling pathways. This review systematically summarizes the structural and functional characteristics of the orexin system, with particular emphasis on the functional divergence of OX1R and OX2R and their therapeutic relevance. Recent advances in dual orexin receptor antagonists (DORAs) and selective orexin receptor antagonists are discussed, and the pharmacological properties and clinical performance of approved and investigational agents are compared. In addition, the safety profiles, adverse effects, and clinical limitations of ORAs are reviewed. Future perspectives are highlighted, including receptor selectivity, pharmacokinetic optimization, and personalized treatment strategies. Collectively, ORAs offer a mechanism-based therapeutic approach that may improve both the efficacy and safety of insomnia treatment.<\/jats:p>","DOI":"10.3390\/molecules31162795","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T11:51:36Z","timestamp":1786449096000},"page":"2795","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Research Progress and Future Perspectives of Orexin Receptor Antagonists in Insomnia Therapy"],"prefix":"10.3390","volume":"31","author":[{"given":"Zirui","family":"Zhang","sequence":"first","affiliation":[{"name":"Academy of Pharmacy, Xi\u2019an Jiaotong-Liverpool University, Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Zhu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Gao","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caoqing","family":"Ji","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Ling","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,11]]},"reference":[{"key":"ref_1","unstructured":"(2026, April 14). China News Service. Available online: https:\/\/wap.chinanews.com\/wap\/detail\/chs\/zw\/9847821heixhindf.shtml."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/S1474-4422(15)00021-6","article-title":"The Neurobiology, Investigation, and Treatment of Chronic Insomnia","volume":"14","author":"Riemann","year":"2015","journal-title":"Lancet Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1207\/S15402010BSM0104_2","article-title":"Self-efficacy and adherence to cognitive-behavioral treatment of insomnia","volume":"1","author":"Bouchard","year":"2003","journal-title":"Behav. Sleep Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"116395","DOI":"10.1016\/j.bcp.2024.116395","article-title":"GPR56: A Potential Therapeutic Target for Neurological and Psychiatric Disorders","volume":"226","author":"Qi","year":"2024","journal-title":"Biochem. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"295","DOI":"10.2174\/011570159X370669250526115723","article-title":"The Role of Trace Amine-Associated Receptor 1 (TAAR1) in the Pathophysiology and Treatment of Depression","volume":"24","author":"Guan","year":"2026","journal-title":"Curr. Neuropharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Chen, X., Hu, K., Shi, H.-Z., He, S.-M., Yang, Y., Yang, C.-W., Zhang, Y., Tian, X., Li, Y., and Gao, Y.H. (2025). The effect of zopiclone co-administration on sertraline initial dosage optimization in pediatric major depressive disorder patients based on model-informed precision dosing. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1470865"},{"key":"ref_7","first-page":"678","article-title":"Effects of Electroacupuncture on Hypothalamic Neurotransmitters in Insomnia Rats","volume":"34","author":"Jiang","year":"2015","journal-title":"Shanghai J. Acupunct. Moxibustion"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"115800","DOI":"10.1016\/j.biopha.2023.115800","article-title":"Current status of GABA receptor subtypes in analgesia","volume":"168","author":"Qian","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e200452","DOI":"10.1212\/CPJ.0000000000200452","article-title":"Benzodiazepine Initiation and the Risk of Falls or Fall-Related Injuries in Older Adults Following Acute Ischemic Stroke","volume":"15","author":"Sun","year":"2025","journal-title":"Neurol. Clin. Pract."},{"key":"ref_10","first-page":"560","article-title":"Chinese Guidelines for Diagnosis and Treatment of Insomnia in Adults","volume":"2024","author":"Society","year":"2023","journal-title":"Chin. J. Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"\u017be\u0142abowski, K., Pichowicz, W., Skowron, I., Szwach, J., Biedka, K., Weso\u0142owski, M., B\u0142aszczyk, K., Ziobro, O., Petrov, W., and Kuku\u0142a-Koch, W. (2025). The Efficacy of Melatonergic Receptor Agonists Used in Clinical Practice in Insomnia Treatment: Melatonin, Tasimelteon, Ramelteon, Agomelatine, and Selected Herbs. Molecules, 30.","DOI":"10.3390\/molecules30183814"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"112590","DOI":"10.1016\/j.biopha.2021.112590","article-title":"Prednisolone Induces Sleep Disorders via Inhibition of Melatonin Secretion by the Circadian Rhythm in Zebrafish","volume":"147","author":"Jiang","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1177\/10398562221092310","article-title":"Lemborexant, an Orexin Receptor Antagonist Sedative-Hypnotic: Is It Useful for Insomnia in Psychiatric Disorders?","volume":"30","author":"Keks","year":"2022","journal-title":"Australas. Psychiatry"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"111274","DOI":"10.1016\/j.biopha.2021.111274","article-title":"Melatonin Attenuates Oxidative Stress and Inflammation of M\u00fcller Cells in Diabetic Retinopathy via Activating the Sirt1 Pathway","volume":"137","author":"Tu","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"92","DOI":"10.9734\/indj\/2024\/v21i6457","article-title":"Orexants, Orexin Receptor Antagonists: Novel Therapeutic Agents for Insomnia Disorder","volume":"21","author":"Kandukuri","year":"2024","journal-title":"Int. Neuropsychiatr. Dis. J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1111\/jnc.14568","article-title":"Orexins Increase the Firing Activity of Nigral Dopaminergic Neurons and Participate in Motor Control in Rats","volume":"147","author":"Liu","year":"2018","journal-title":"J. Neurochem."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"\u017be\u0142abowski, K., Petrov, W., Wojtysiak, K., Ratka, Z., Biedka, K., Weso\u0142owski, M., Fus, K., \u015alebioda, D., Rusinek, M., and Sterkowicz, M. (2025). Targeting the Orexin System in the Pharmacological Management of Insomnia and Other Diseases: Suvorexant, Lemborexant, Daridorexant, and Novel Experimental Agents. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26178700"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Gotter, A.L., Garson, S.L., Stevens, J., Munden, R.L., Fox, S.V., Tannenbaum, P.L., Yao, L., Kuduk, S.D., McDonald, T., and Uslaner, J.M. (2014). Differential Sleep-Promoting Effects of Dual Orexin Receptor Antagonists and GABAA Receptor Modulators. BMC Neurosci., 15.","DOI":"10.1186\/1471-2202-15-109"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/s41782-025-00320-y","article-title":"Orexin receptor antagonists and insomnia","volume":"9","author":"Saibaba","year":"2025","journal-title":"Sleep Vigil."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"174117","DOI":"10.1016\/j.pbb.2025.174117","article-title":"Dual orexin receptor antagonists in insomnia: Toward a new therapeutic paradigm","volume":"258","author":"Chaki","year":"2026","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"410","DOI":"10.18203\/2319-2003.ijbcp20260447","article-title":"A review on orexin receptor antagonists in chronic insomnia: A revolutionary approach","volume":"15","author":"Humbi","year":"2026","journal-title":"Int. J. Basic Clin. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/S0092-8674(00)80949-6","article-title":"Orexins and Orexin Receptors: A Family of Hypothalamic Neuropeptides and G Protein-Coupled Receptors That Regulate Feeding Behavior","volume":"92","author":"Sakurai","year":"1998","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e40213","DOI":"10.1097\/MD.0000000000040213","article-title":"Bibliometric analysis of orexin: A promising neuropeptide","volume":"103","author":"Sun","year":"2024","journal-title":"Medicine"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Nakamachi, T. (2016). Orexin. Handbook of Hormones, Elsevier.","DOI":"10.1016\/B978-0-12-801028-0.00127-6"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1146\/annurev-pharmtox-010510-100528","article-title":"Orexin Receptors: Pharmacology and Therapeutic Opportunities","volume":"51","author":"Scammell","year":"2011","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1124\/pr.111.005546","article-title":"International Union of Basic and Clinical Pharmacology. LXXXVI. Orexin receptor function, nomenclature and pharmacology","volume":"64","author":"Gotter","year":"2012","journal-title":"Pharmacol. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1038\/nature14035","article-title":"Crystal structure of the human OX2 orexin receptor bound to the insomnia drug suvorexant","volume":"519","author":"Yin","year":"2015","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1038\/nrn3837","article-title":"The Role of Orexin in Motivated Behaviours","volume":"15","author":"Sakurai","year":"2014","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.neuropharm.2008.06.060","article-title":"Role of Lateral Hypothalamic Orexin Neurons in Reward Processing and Addiction","volume":"56","author":"Smith","year":"2009","journal-title":"Neuropharmacology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"232","DOI":"10.2174\/187152709788921726","article-title":"The Sleep-Wake Cycle, the Hypocretin\/Orexin System and Narcolepsy: Advances from Preclinical Research to Treatment","volume":"8","author":"Bradbury","year":"2009","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"6518","DOI":"10.1523\/JNEUROSCI.6506-10.2011","article-title":"Differential Roles of Orexin Receptor-1 and -2 in the Regulation of Non-REM and REM Sleep","volume":"31","author":"Mieda","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1016\/S0896-6273(03)00330-1","article-title":"Distinct Narcolepsy Syndromes in Orexin Receptor-2 and Orexin Null Mice","volume":"38","author":"Willie","year":"2003","journal-title":"Neuron"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"106682","DOI":"10.1016\/j.vascn.2020.106682","article-title":"Systematic Characterization of AT1 Receptor Antagonists with Label-Free Dynamic Mass Redistribution Assays","volume":"102","author":"Qu","year":"2020","journal-title":"J. Pharmacol. Toxicol. Methods"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1528","DOI":"10.1021\/acs.jmedchem.9b01787","article-title":"Comparison of Orexin 1 and Orexin 2 Ligand Binding Modes Using X-Ray Crystallography and Computational Analysis","volume":"63","author":"Rappas","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1038\/s41467-021-21087-6","article-title":"Structures of Active-State Orexin Receptor 2 Rationalize Peptide and Small-Molecule Agonist Recognition and Receptor Activation","volume":"12","author":"Hong","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1080\/23328940.2015.1066921","article-title":"Thermoregulation under Pressure: A Role for Orexin Neurons","volume":"2","author":"Kuwaki","year":"2015","journal-title":"Temperature"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1002\/j.2040-4603.2020.tb00118.x","article-title":"Orexin in Respiratory and Autonomic Regulation, Health and Diseases","volume":"10","author":"Barnett","year":"2020","journal-title":"Compr. Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"17771","DOI":"10.1074\/jbc.274.25.17771","article-title":"Structure and Function of Human Prepro-Orexin Gene","volume":"274","author":"Sakurai","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"565","DOI":"10.5483\/BMBRep.2004.37.5.565","article-title":"Solution Structure of Human Orexin-A: Regulator of Appetite and Wakefulness","volume":"37","author":"Kim","year":"2004","journal-title":"BMB Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1046\/j.1432-1327.1999.00911.x","article-title":"Solution Structure of a New Hypothalamic Neuropeptide, Human Hypocretin-2\/orexin-B","volume":"266","author":"Lee","year":"1999","journal-title":"Eur. J. Biochem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/S0014-2999(02)01429-2","article-title":"Orexins and the Treatment of Obesity","volume":"440","author":"Smart","year":"2002","journal-title":"Eur. J. Pharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"179ra44","DOI":"10.1126\/scitranslmed.3005213","article-title":"Orexin Receptor Antagonists Differ from Standard Sleep Drugs by Promoting Sleep at Doses That Do Not Disrupt Cognition","volume":"5","author":"Uslaner","year":"2013","journal-title":"Sci. Transl. Med."},{"key":"ref_43","first-page":"1149","article-title":"Research progress of orexin receptor antagonists in the treatment of insomnia","volume":"27","author":"Pan","year":"2020","journal-title":"Chin. J. Prim. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1146\/annurev-pharmtox-040323-031929","article-title":"Orexin Receptor Antagonism: Normalizing Sleep Architecture in Old Age and Disease","volume":"64","author":"Kron","year":"2024","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_45","first-page":"1467","article-title":"Drug research on dual orexin receptor modulation in sleep-wake disorders: Bidirectional regulation strategies from antagonists to agonists","volume":"30","author":"Tang","year":"2025","journal-title":"Chin. J. Clin. Pharmacol. Ther."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1080\/17425255.2020.1817380","article-title":"Clinical Pharmacology, Efficacy, and Safety of Orexin Receptor Antagonists for the Treatment of Insomnia Disorders","volume":"16","author":"Muehlan","year":"2020","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Gozzi, A., Turrini, G., Piccoli, L., Massagrande, M., Amantini, D., Antolini, M., Martinelli, P., Cesari, N., Montanari, D., and Tessari, M. (2011). Functional magnetic resonance imaging reveals different neural substrates for the effects of orexin-1 and orexin-2 receptor antagonists. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0016406"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Osman, M., Alqatam, H., Banerjee, S., and Kar, N. (2026). Safety, efficacy, and potential clinical application of nivasorexant, a novel orexin receptor antagonist, in psychiatry: A Systematic Review. Ind. Psychiatry J., ahead of print.","DOI":"10.4103\/ipj.ipj_266_25"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"5809","DOI":"10.1016\/j.bmcl.2016.10.019","article-title":"Discovery of Highly Potent and Selective Orexin 1 Receptor Antagonists (1-SORAs) Suitable for In Vivo Interrogation of Orexin 1 Receptor Pharmacology","volume":"26","author":"Stump","year":"2016","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s10822-014-9710-x","article-title":"Shaping suvorexant: Application of experimental and theoretical methods for driving synthetic designs","volume":"28","author":"McGaughey","year":"2014","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1124\/jpet.117.241422","article-title":"In vitro and in silico characterization of lemborexant (E2006), a Novel Dual Orexin Receptor Antagonist","volume":"362","author":"Beuckmann","year":"2017","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"5320","DOI":"10.1021\/jm100541c","article-title":"Discovery of the Dual Orexin Receptor Antagonist [(7R)-4-(5-Chloro-1,3-Benzoxazol-2-Yl)-7-Methyl-1,4-Diazepan-1-Yl][5-Methyl-2-(2H-1,2,3-Triazol-2-Yl)Phenyl]Methanone (MK-4305) for the Treatment of Insomnia","volume":"53","author":"Cox","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.biopsych.2014.10.003","article-title":"Suvorexant in Patients with Insomnia: Results from Two 3-Month Randomized Controlled Clinical Trials","volume":"79","author":"Herring","year":"2016","journal-title":"Biol. Psychiatry"},{"key":"ref_54","first-page":"152","article-title":"Structure optimization strategy of dual orexin receptor antagonist hypnotic drugs","volume":"42","author":"Wang","year":"2023","journal-title":"Chin. J. New Drugs Clin. Remedies"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2132","DOI":"10.1002\/cmdc.201600175","article-title":"Discovery of highly potent dual orexin receptor antagonists via a scaffold-hopping approach","volume":"11","author":"Heidmann","year":"2016","journal-title":"ChemMedChem"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"e1918254","DOI":"10.1001\/jamanetworkopen.2019.18254","article-title":"Comparison of Lemborexant with Placebo and Zolpidem Tartrate Extended Release for the Treatment of Older Adults with Insomnia Disorder: A Phase 3 Randomized Clinical Trial: A Phase 3 Randomized Clinical Trial","volume":"2","author":"Rosenberg","year":"2019","journal-title":"JAMA Netw. Open"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"106523","DOI":"10.1016\/j.sleep.2025.106523","article-title":"Effect of Daridorexant on Nighttime Wakefulness and Next-Morning Sleepiness: Assessing the Transition from Night to Day in Insomnia Disorder","volume":"131","author":"Dauvilliers","year":"2025","journal-title":"Sleep Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1124\/jpet.117.241596","article-title":"The Use of Physiology-Based Pharmacokinetic and Pharmacodynamic Modeling in the Discovery of the Dual Orexin Receptor Antagonist ACT-541468","volume":"362","author":"Treiber","year":"2017","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_59","first-page":"1401","article-title":"New drug for sleep disorders\u2014Daridorexant hydrochloride","volume":"41","author":"Chen","year":"2022","journal-title":"Her. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"zsab224","DOI":"10.1093\/sleep\/zsab224","article-title":"Abuse Potential Assessment of the New Dual Orexin Receptor Antagonist Daridorexant in Recreational Sedative Drug Users as Compared to Suvorexant and Zolpidem","volume":"45","author":"Ufer","year":"2022","journal-title":"Sleep"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1097\/JCP.0000000000001561","article-title":"Abuse Potential of Lemborexant, a Dual Orexin Receptor Antagonist, Compared with Zolpidem and Suvorexant in Recreational Sedative Users","volume":"42","author":"Landry","year":"2022","journal-title":"J. Clin. Psychopharmacol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"117517","DOI":"10.1016\/j.bcp.2025.117517","article-title":"Orexin Receptor 2 (OX2R) Exhibits Ligand-Dependent Spatiotemporal Pharmacology through G\u03b1i\u2013\u03b2-Arrestin Dynamics in Response to Orexin-A and Orexin-B","volume":"243","author":"Dale","year":"2026","journal-title":"Biochem. Pharmacol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"100094","DOI":"10.1016\/j.sleepx.2023.100094","article-title":"Effects of new hypnotic drugs on cognition: A systematic review and network meta-analysis","volume":"6","author":"Zhou","year":"2023","journal-title":"Sleep Med. X"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1055\/s-0043-1770805","article-title":"Daridorexant, a Recently Approved Dual Orexin Receptor Antagonists (DORA) in Treatment of Insomnia","volume":"16","author":"Chakraborty","year":"2023","journal-title":"Sleep Sci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"491","DOI":"10.2147\/NDT.S31495","article-title":"Suvorexant: A promising, novel treatment for insomnia","volume":"12","author":"Parish","year":"2016","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_66","unstructured":"U.S. Food and Drug Administration (2014). Belsomra (Suvorexant) Prescribing Information, Revised Prescribing Information."},{"key":"ref_67","unstructured":"National Institutes of Health (2026, April 14). Lemborexant, StatPearls, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK559070\/."},{"key":"ref_68","unstructured":"European Medicines Agency (2026, April 14). Dayvigo (Lemborexant) Summary of Product Characteristics. Available online: https:\/\/www.ema.europa.eu."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1002\/jcph.297","article-title":"Entry-into-humans study with ACT-462206, a novel dual orexin receptor antagonist, comparing its pharmacodynamics with almorexant","volume":"54","author":"Hoch","year":"2014","journal-title":"J. Clin. Pharmacol."},{"key":"ref_70","unstructured":"U.S. Food and Drug Administration (2022). Quviviq (Daridorexant) Prescribing Information; Revised Prescribing Information."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1111\/bph.12428","article-title":"Melatonin Modulates Microsomal PGE Synthase 1 and NF-E2-related Factor-2-regulated Antioxidant Enzyme Expression in LPS-induced Murine Peritoneal Macrophages","volume":"171","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1038\/nm1544","article-title":"Promotion of sleep by targeting the orexin system in rats, dogs and humans","volume":"13","author":"Dingemanse","year":"2007","journal-title":"Nat. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1016\/j.ejps.2013.06.002","article-title":"Influence of mild and moderate liver impairment on the pharmacokinetics and metabolism of almorexant, a dual orexin receptor antagonist","volume":"49","author":"Hoch","year":"2013","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"pyw022","DOI":"10.1093\/ijnp\/pyw022","article-title":"A Phase II Dose-Ranging Study Evaluating the Efficacy and Safety of the Orexin Receptor Antagonist Filorexant (MK-6096) in Patients with Primary Insomnia","volume":"19","author":"Connor","year":"2016","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Banister, S.D., and Connor, M. (2018). The Chemistry and Pharmacology of Synthetic Cannabinoid Receptor Agonist New Psychoactive Substances: Evolution. Handbook of Experimental Pharmacology, Springer International Publishing.","DOI":"10.1007\/164_2018_144"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"116672","DOI":"10.1016\/j.bcp.2024.116672","article-title":"Evidence for the contribution of vasopressin V1B receptors in the pathophysiology of depression","volume":"231","author":"Guan","year":"2024","journal-title":"Biochem. Pharmacol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1001\/jamapsychiatry.2025.1999","article-title":"Efficacy and Safety of Seltorexant in Insomnia Disorder: A Randomized Clinical Trial","volume":"82","author":"Mesens","year":"2025","journal-title":"JAMA Psychiatry"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.jpsychires.2024.06.029","article-title":"Association between the use of orexin receptor antagonists and falls or fractures: A meta-analysis","volume":"176","author":"Pan","year":"2024","journal-title":"J. Psychiatr. Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"e14017","DOI":"10.1111\/jsr.13902","article-title":"The orexin story and orexin receptor antagonists for the treatment of insomnia","volume":"32","author":"Muehlan","year":"2023","journal-title":"J. Sleep Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1038\/s41398-024-03087-4","article-title":"Orexin receptor antagonists in the treatment of insomnia associated with psychiatric disorders: A systematic review","volume":"14","author":"Kishi","year":"2024","journal-title":"Transl. Psychiatry"},{"key":"ref_81","unstructured":"Shanghai Securities News (2026, April 28). KHN707, a New Insomnia Drug by Kanghong Pharmaceutical, Approved for Clinical Trial. Available online: http:\/\/paper.cnstock.com\/html\/2026-02\/26\/content_2182308.htm."},{"key":"ref_82","unstructured":"Health Times (2026, April 28). Kanghong Pharmaceutical\u2019s Insomnia New Drug KHN707 Tablet Approved for Clinical Trial. Available online: http:\/\/www.jksb.com.cn\/html\/news\/industry\/2026\/0226\/251269.html."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1007\/s40429-024-00598-4","article-title":"Improving Sleep to Address Co-Occurring Substance Use Disorder and Chronic Pain: Exploring the Potential of the Orexin (Hypocretin) System as a Clinical Target","volume":"11","author":"Sun","year":"2024","journal-title":"Curr. Addict. Rep."},{"key":"ref_84","unstructured":"National Library of Medicine (US) (2025). NCT07132086: Prospective Observational Study on the Effectiveness of Daridorexant in Chronic Insomnia in a Real-World Setting [EB\/OL]."},{"key":"ref_85","unstructured":"Chinese Clinical Trial Registry (2026, May 31). A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter, Phase 3 Clinical Study to Evaluate the Efficacy and Safety of YZJ-1139 (Fazamorexant) Tablets in the Treatment of Insomnia Disorder. ChiCTR: CTR20212685. Available online: https:\/\/www.chictr.org.cn."},{"key":"ref_86","unstructured":"ClinicalTrials.gov (2026, May 31). A Study of YZJ-1139 (Fazamorexant) in Adults with Insomnia Disorder. NCT05525637, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05525637."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1177\/0269881115609015","article-title":"Psychomotor effects, pharmacokinetics and safety of the orexin receptor antagonist suvorexant administered in combination with alcohol in healthy subjects","volume":"29","author":"Sun","year":"2015","journal-title":"J. Psychopharmacol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"101332","DOI":"10.1016\/j.smrv.2020.101332","article-title":"Effects of Orexin Receptor Antagonism on Human Sleep Architecture: A Systematic Review","volume":"53","author":"Clark","year":"2020","journal-title":"Sleep Med. Rev."},{"key":"ref_89","first-page":"e97174","article-title":"Real-World Effectiveness and Safety of Daridorexant in Japanese Patients with Insomnia: A Multicenter Observational Study Evaluating Four-Week Changes in Athens Insomnia Scale Among 54 Participants","volume":"17","author":"Kono","year":"2025","journal-title":"Cureus"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Kohlmeier, K.A., Tyler, C.J., Kalogiannis, M., Ishibashi, M., Kristensen, M.P., Gumenchuk, I., Chemelli, R.M., Kisanuki, Y.Y., Yanagisawa, M., and Leonard, C.S. (2013). Differential Actions of Orexin Receptors in Brainstem Cholinergic and Monoaminergic Neurons Revealed by Receptor Knockouts: Implications for Orexinergic Signaling in Arousal and Narcolepsy. Front. Neurosci., 7.","DOI":"10.3389\/fnins.2013.00246"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"4179","DOI":"10.2174\/1381612827666210715155809","article-title":"The intracellular mechanism of berberine-induced inhibition of CYP3A4 activity","volume":"27","author":"Feng","year":"2021","journal-title":"Curr. Pharm. Des."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.neurobiolaging.2016.01.007","article-title":"Rapid Eye Movement Sleep Disruption and Sleep Fragmentation Are Associated with Increased Orexin-A Cerebrospinal Fluid Levels in Mild Cognitive Impairment Due to Alzheimer\u2019s Disease","volume":"40","author":"Liguori","year":"2016","journal-title":"Neurobiol. Aging"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Jiang, M., Li, H., and Kong, L. (2024). Data Mining and Safety Analysis of Dual Orexin Receptor Antagonists (DORAs): A Real-World Pharmacovigilance Study Based on the FAERS Database. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1436405"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s40263-022-00980-8","article-title":"Long-term safety and tolerability of daridorexant in patients with insomnia disorder","volume":"37","author":"Kunz","year":"2023","journal-title":"CNS Drugs"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1111\/cts.13470","article-title":"Effect of Discontinuation of Lemborexant Following Long-Term Treatment of Insomnia Disorder: Secondary Analysis of a Randomized Clinical Trial","volume":"16","author":"Takaesu","year":"2023","journal-title":"Clin. Transl. Sci."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/s41398-025-03439-8","article-title":"Comparative Efficacy and Safety of Daridorexant, Lemborexant, and Suvorexant for Insomnia: A Systematic Review and Network Meta-Analysis","volume":"15","author":"Kishi","year":"2025","journal-title":"Transl. Psychiatry"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"108675","DOI":"10.1016\/j.intimp.2022.108675","article-title":"A Bioactive Gypenoside (GP-14) Alleviates Neuroinflammation and Blood Brain Barrier (BBB) Disruption by Inhibiting the NF-\u03baB Signaling Pathway in a Mouse High-Altitude Cerebral Edema (HACE) Model","volume":"107","author":"Geng","year":"2022","journal-title":"Int. Immunopharmacol."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Hong, H., Lu, X., Lu, Q., Huang, C., and Cui, Z. (2022). Potential Therapeutic Effects and Pharmacological Evidence of Sinomenine in Central Nervous System Disorders. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.1015035"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Hong, H., Lu, X., Wu, C., Chen, J., Chen, C., Zhang, J., Huang, C., and Cui, Z. (2022). A Review for the Pharmacological Effects of Paeoniflorin in the Nervous System. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.898955"},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Liu, Y., Tang, W., Ji, C., Gu, J., Chen, Y., Huang, J., Zhao, X., Sun, Y., Wang, C., and Guan, W. (2021). The Selective SIK2 Inhibitor ARN-3236 Produces Strong Antidepressant-Like Efficacy in Mice via the Hippocampal CRTC1-CREB-BDNF Pathway. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.624429"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"404","DOI":"10.2174\/011570159X371235250417051313","article-title":"Hydroxychloroquine Prevents High-Altitude Cerebral Edema by Inhibiting Endothelial Claudin-5 Autophagic Degradation","volume":"24","author":"Xue","year":"2026","journal-title":"Curr. Neuropharmacol."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/16\/2795\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T11:52:12Z","timestamp":1786449132000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/16\/2795"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,11]]},"references-count":101,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["molecules31162795"],"URL":"https:\/\/doi.org\/10.3390\/molecules31162795","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,11]]}}}