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Preclinical evidence suggests that the orexin system, and particularly the orexin-1 receptor (OX1R), may be involved in the pathophysiology of panic and anxiety. Selective OX1R antagonists thus may constitute a potential new treatment strategy for panic- and anxiety-related disorders. Here, we characterized a novel selective OX1R antagonist, JNJ-61393215, and determined its affinity and potency for human and rat OX1R in vitro. We also evaluated the safety, pharmacokinetic, and pharmacodynamic properties of JNJ-61393215 in first-in-human single- and multiple-ascending dose studies conducted. Finally, the potential anxiolytic effects of JNJ-61393215 were evaluated both in rats and in healthy men using 35% CO<jats:sub>2<\/jats:sub> inhalation challenge to induce panic symptoms. In the rat CO<jats:sub>2<\/jats:sub> model of panic anxiety, JNJ-61393215 demonstrated dose-dependent attenuation of CO<jats:sub>2<\/jats:sub>-induced panic-like behavior without altering baseline locomotor or autonomic activity, and had minimal effect on spontaneous sleep. In phase-1 human studies, JNJ-61393215 at 90\u2009mg demonstrated significant reduction (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.02) in CO<jats:sub>2<\/jats:sub>-induced fear and anxiety symptoms that were comparable to those obtained using alprazolam. The most frequently reported adverse events were somnolence and headache, and all events were mild in severity. These results support the safety, tolerability, and anxiolytic effects of JNJ-61393215, and validate CO<jats:sub>2<\/jats:sub> exposure as a translational cross-species experimental model to evaluate the therapeutic potential of novel anxiolytic drugs.<\/jats:p>","DOI":"10.1038\/s41398-020-00937-9","type":"journal-article","created":{"date-parts":[[2020,9,7]],"date-time":"2020-09-07T12:02:48Z","timestamp":1599480168000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Translational evaluation of novel selective orexin-1 receptor antagonist JNJ-61393215 in an experimental model for panic in rodents and humans"],"prefix":"10.1038","volume":"10","author":[{"given":"Giacomo","family":"Salvadore","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2971-6152","authenticated-orcid":false,"given":"Pascal","family":"Bonaventure","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anantha","family":"Shekhar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip L.","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Lord","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brock T.","family":"Shireman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terry P.","family":"Lebold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane","family":"Nepomuceno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Dugovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sander","family":"Brooks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rob","family":"Zuiker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathy","family":"Bleys","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanaka","family":"Tatikola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart","family":"Remmerie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel E.","family":"Jacobs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koen","family":"Schruers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Moyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail","family":"Nash","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luc G. 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A.S. has received research awards from Eli Lilly and Co., Johnson & Johnson, and AstraZeneca. R.Z., S.B., and G.E.J. were the study investigators and employees of CHDR; P.J. and K.S. do not have any conflict of interests to declare. All authors participated in the original design of the studies, supervising recruitment and monitoring of data quality, and contributed to the data interpretation, development, and review of this paper, and confirm that they have read the journal\u2019s position on issues involved in ethical publication, and affirm that this report is consistent with those guidelines. All authors met ICMJE criteria, and all those who fulfilled those criteria are listed as authors. All authors had access to the study data, provided direction, and comments on the paper, made the final decision about where to publish these data, and approved submission to this journal.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"308"}}