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Their effects are mediated by two distinct G protein\u2010coupled receptors, namely orexin receptor type 1 (OX1\u2010R) and type 2 (OX2\u2010R), which share 64% amino acid identity. Given the wide expression of OX\u2010Rs in different central nervous system and peripheral areas and the several\u00a0pathophysiological functions in which they are involved, including sleep\u2010wake cycle regulation (mainly mediated by OX2\u2010R), emotion, panic\u2010like behaviors, anxiety\/stress, food intake, and energy homeostasis (mainly mediated by OX1\u2010R), both subtypes represent targets of interest for many structure\u2013activity relationship (SAR) campaigns carried out by pharmaceutical companies and academies. However, before 2017 the research was predominantly directed towards dual\u2010orexin ligands, and limited chemotypes were investigated. Analytical characterizations, including resolved structures for both OX1\u2010R and OX2\u2010R in complex with agonists and antagonists, have improved the understanding of the molecular basis of receptor recognition and are assets for medicinal chemists in the design of subtype\u2010selective ligands. This review is focused on the medicinal chemistry aspects of small molecules acting as dual or subtype selective OX1\u2010R\/OX2\u2010R agonists and antagonists belonging to different chemotypes and developed in the last years, including radiolabeled OX\u2010R ligands for molecular imaging. Moreover, the pharmacological effects of the most studied ligands in different neuropsychiatric diseases, such as sleep, mood, substance use, and eating disorders, as well as pain, have been discussed. Poly\u2010pharmacology applications and multitarget ligands have also been considered.<\/jats:p>","DOI":"10.1002\/med.21959","type":"journal-article","created":{"date-parts":[[2023,4,10]],"date-time":"2023-04-10T06:44:54Z","timestamp":1681109094000},"page":"1607-1667","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Targeting orexin receptors: Recent advances in the development of subtype selective or dual ligands for the treatment of neuropsychiatric disorders"],"prefix":"10.1002","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7306-0114","authenticated-orcid":false,"given":"Alessandro","family":"Bonifazi","sequence":"first","affiliation":[{"name":"Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse \u2013 Intramural Research Program National Institutes of Health Baltimore Maryland United 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