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Therapeutic strategies targeting the relaxin\u20103 peptide or its primary endogenous receptor, RXFP3, for the treatment of major depression and anxiety disorders have been limited by a lack of compounds with drug\u2010like properties. We proposed that a hydrocarbon\u2010stapled mimetic of relaxin\u20103, when administered intranasally, might be uniquely applicable to the treatment of these disorders.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>We designed a series of hydrocarbon\u2010stapled relaxin\u20103 mimetics and identified the most potent compound using in vitro receptor binding and activation assays. Further, we assessed the effect of intranasal delivery of relaxin\u20103 and the lead stapled mimetic in rat models of anxiety and depression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>We developed an <jats:italic>i<\/jats:italic>,<jats:italic>i<\/jats:italic>+7 stapled relaxin\u20103 mimetic that manifested a stabilized \u03b1\u2010helical structure, proteolytic resistance, and confirmed agonist activity in receptor binding and activation in vitro assays. The stapled peptide agonist enhanced food intake after intracerebral infusion in rats, confirming in vivo activity. We showed that intranasal delivery of the lead <jats:italic>i<\/jats:italic>,<jats:italic>i<\/jats:italic>+7 stapled peptide or relaxin\u20103 had orexigenic effects in rats, indicating a potential clinically translatable route of delivery. Further, intranasal administration of the lead <jats:italic>i<\/jats:italic>,<jats:italic>i<\/jats:italic>+7 stapled peptide exerted anxiolytic and antidepressant\u2010like activity in anxiety\u2010 and depression\u2010related behaviour paradigms.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Our preclinical findings demonstrate that targeting the relaxin\u20103\/RXFP3 receptor system via intranasal delivery of an <jats:italic>i<\/jats:italic>,<jats:italic>i<\/jats:italic>+7 stapled relaxin\u20103 mimetic may represent an effective treatment approach for depression, anxiety, and related neuropsychiatric disorders.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14774","type":"journal-article","created":{"date-parts":[[2019,6,20]],"date-time":"2019-06-20T16:04:53Z","timestamp":1561046693000},"page":"3899-3923","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Intranasal administration of a stapled relaxin\u20103 mimetic has anxiolytic\u2010 and antidepressant\u2010like activity in rats"],"prefix":"10.1111","volume":"176","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1447-8203","authenticated-orcid":false,"given":"Subhi","family":"Marwari","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Yong Loo Lin School of Medicine National University of Singapore  Singapore"},{"name":"Department of Pharmacy, Faculty of Science National University of Singapore  Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anders","family":"Poulsen","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Experimental Therapeutics Centre Agency for Science, Technology and Research (A*STAR)  Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norrapat","family":"Shih","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Faculty of Science National University of Singapore  Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rajamani","family":"Lakshminarayanan","sequence":"additional","affiliation":[{"name":"Anti\u2010Infectives Research Group, Singapore Eye Research Institute  Singapore"},{"name":"Ophthalmology and Visual Sciences Academic Clinical Program Duke\u2010NUS Medical School  Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R. 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