{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T03:14:51Z","timestamp":1788318891934,"version":"build-2803163510"},"reference-count":36,"publisher":"American Chemical Society (ACS)","issue":"8","license":[{"start":{"date-parts":[[2015,6,25]],"date-time":"2015-06-25T00:00:00Z","timestamp":1435190400000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"publisher","award":["MH081247-01"],"award-info":[{"award-number":["MH081247-01"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,8,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Modulation of the neuropeptide S (NPS) system has been linked to a variety of CNS disorders such as panic disorder, anxiety, sleeping disorders, asthma, obesity, PTSD, and substance abuse. In this study, a series of diphenyltetrahydro-1H-oxazolo[3,4-\u03b1]pyrazin-3(5H)-ones were synthesized and evaluated for antagonist activity at the neuropeptide S receptor. The absolute configuration was determined by chiral resolution of the key synthetic intermediate, followed by analysis of one of the individual enantiomers by X-ray crystallography. The R isomer was then converted to a biologically active compound (34) that had a Ke of 36 nM. The most potent compound displayed enhanced aqueous solubility compared with the prototypical antagonist SHA-68 and demonstrated favorable pharmacokinetic properties for behavioral assessment. In vivo analysis in mice indicated a significant blockade of NPS induced locomotor activity at an ip dose of 50 mg\/kg. This suggests that analogs having improved drug-like properties will facilitate more detailed studies of the neuropeptide S receptor system.<\/jats:p>","DOI":"10.1021\/cn500113c","type":"journal-article","created":{"date-parts":[[2014,6,25]],"date-time":"2014-06-25T13:10:46Z","timestamp":1403701846000},"page":"731-744","source":"Crossref","is-referenced-by-count":12,"title":["Identification of Neuropeptide S Antagonists: Structure\u2013Activity Relationship\nStudies, X-ray Crystallography, and in Vivo Evaluation"],"prefix":"10.1021","volume":"5","author":[{"given":"Carla","family":"Hassler","sequence":"first","affiliation":[{"name":"Research Triangle Institute , Post Office Box 12194, , ,","place":["Research Triangle Park, North Carolina, United States, 27709-2194"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Research Triangle Institute , Post Office Box 12194, , ,","place":["Research Triangle Park, North Carolina, United States, 27709-2194"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Gilmour","sequence":"additional","affiliation":[{"name":"Research Triangle Institute , Post Office Box 12194, , ,","place":["Research Triangle Park, North Carolina, United States, 27709-2194"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler","family":"Graf","sequence":"additional","affiliation":[{"name":"Research Triangle Institute , Post Office Box 12194, , ,","place":["Research Triangle Park, North Carolina, United States, 27709-2194"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Fennell","sequence":"additional","affiliation":[{"name":"Research Triangle Institute , Post Office Box 12194, , ,","place":["Research Triangle Park, North Carolina, United States, 27709-2194"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodney","family":"Snyder","sequence":"additional","affiliation":[{"name":"Research Triangle Institute , Post Office Box 12194, , ,","place":["Research Triangle Park, North Carolina, United States, 27709-2194"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey R.","family":"Deschamps","sequence":"additional","affiliation":[{"name":"Naval Research Laboratory , , Code 6930, 4555 Overlook Avenue SW , , ,","place":["Washington, DC, United States, 20375"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rainer K.","family":"Reinscheid","sequence":"additional","affiliation":[{"name":"University of California, Irvine , , 2214 Natural Sciences I , Mail Code: 3958, , ,","place":["Irvine, California, United States, 92697-3958"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celia","family":"Garau","sequence":"additional","affiliation":[{"name":"University of California, Irvine , , 2214 Natural Sciences I , Mail Code: 3958, , ,","place":["Irvine, California, United States, 92697-3958"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott P.","family":"Runyon","sequence":"additional","affiliation":[{"name":"Research Triangle Institute , Post Office Box 12194, , ,","place":["Research Triangle Park, North Carolina, United States, 27709-2194"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2014,6,25]]},"reference":[{"key":"2026090122392020200_cit1","unstructured":"Sato, S.; Shintani, Y.; Miyajima, N.; Yoshimura, K., Novel G-protein\ncoupled receptor protein and DNA thereof. 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Behav."},{"issue":"5","key":"2026090122392020200_cit21","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1111\/j.1478-3231.2009.02027_1.x","article-title":"Is albumin infusion necessary after\nlarge volume paracentesis?","volume":"29","author":"Cardenas","year":"2009","journal-title":"Liver Int."},{"issue":"5","key":"2026090122392020200_cit21a","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1111\/j.1478-3231.2009.02027_1.x","volume":"29","author":"Cardenas","year":"2009","journal-title":"Liver Int."},{"key":"2026090122392020200_cit22","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1111\/j.1471-4159.2010.06947.x","article-title":"Neuropeptide\nS stimulates dopaminergic neurotransmission in the medial prefrontal\ncortex","volume":"115","author":"Si","year":"2010","journal-title":"J. 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Neurosci."},{"issue":"45","key":"2026090122392020200_cit25","doi-asserted-by":"crossref","first-page":"19567","DOI":"10.1073\/pnas.1004100107","article-title":"Neuropeptide\nS facilitates cue-induced relapse to cocaine seeking through activation\nof the hypothalamic hypocretin system","volume":"107","author":"Kallupi","year":"2010","journal-title":"Proc.\nNatl. Acad. Sci. U. S. A."},{"issue":"3","key":"2026090122392020200_cit26","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1124\/jpet.107.135103","article-title":"Synthesis and pharmacological in vitro and in vivo\nprofile of 3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic\nacid 4-fluoro-benzylamide (SHA 68), a selective antagonist of the\nneuropeptide S receptor","volume":"325","author":"Okamura","year":"2008","journal-title":"J. Pharmacol. Exp.\nTher."},{"issue":"14","key":"2026090122392020200_cit27","doi-asserted-by":"crossref","first-page":"4064","DOI":"10.1016\/j.bmcl.2008.05.098","article-title":"Identifying structural\nfeatures on 1,1-diphenyl-hexahydro-oxazolo[3,4-a]pyrazin-3-ones critical\nfor Neuropeptide S antagonist activity","volume":"18","author":"Zhang","year":"2008","journal-title":"Bioorg.\nMed. Chem. Lett."},{"issue":"15","key":"2026090122392020200_cit28","doi-asserted-by":"crossref","first-page":"4700","DOI":"10.1016\/j.bmcl.2010.04.143","article-title":"Synthesis\nand evaluation of a new series of Neuropeptide S receptor antagonists","volume":"20","author":"Melamed","year":"2010","journal-title":"Bioorg. Med. Chem. Lett."},{"issue":"15","key":"2026090122392020200_cit29","doi-asserted-by":"crossref","first-page":"4704","DOI":"10.1016\/j.bmcl.2010.04.016","article-title":"Tricyclic imidazole\nantagonists of the Neuropeptide S Receptor","volume":"20","author":"Trotter","year":"2010","journal-title":"Bioorg. Med. Chem. Lett."},{"issue":"24","key":"2026090122392020200_cit30","doi-asserted-by":"crossref","first-page":"7308","DOI":"10.1016\/j.bmcl.2010.10.067","article-title":"Synthesis and pharmacological characterization\nof 5-phenyl-2-[2-(1-piperidinylcarbonyl)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-c]imidazo\nl-1-ones: a new class of Neuropeptide S antagonists","volume":"20","author":"Micheli","year":"2010","journal-title":"Bioorg. Med. Chem. Lett."},{"issue":"24","key":"2026090122392020200_cit31","doi-asserted-by":"crossref","first-page":"10132","DOI":"10.1523\/JNEUROSCI.4742-12.2013","article-title":"A novel brain\npenetrant NPS receptor antagonist, NCGC00185684, blocks alcohol-induced\nERK-phosphorylation in the central amygdala and decreases operant\nalcohol self-administration in rats","volume":"33","author":"Thorsell","year":"2013","journal-title":"J. Neurosci."},{"issue":"51","key":"2026090122392020200_cit32","doi-asserted-by":"crossref","first-page":"9407","DOI":"10.1016\/S0040-4039(98)02194-7","article-title":"Isocyanates.\nPart 5. Synthesis of chiral oxazolidin-2-ones\nand imidazolidin-2-ones via DMAP-catalyzed isocyanation of amines\nwith di-tert-butyl dicarbonate","volume":"39","author":"Kno\u0308lker","year":"1998","journal-title":"Tetrahedron\nLett."},{"issue":"1","key":"2026090122392020200_cit33","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1081\/DDC-100000135","article-title":"Determination of\nthe aqueous solubility of drugs using a convenient 96-well plate-based\nassay","volume":"27","author":"Roy","year":"2001","journal-title":"Drug Dev. Ind. Pharm."},{"issue":"8","key":"2026090122392020200_cit34","doi-asserted-by":"crossref","first-page":"2738","DOI":"10.1021\/jm200138r","article-title":"Synthesis and separation\nof the enantiomers of the neuropeptide S receptor antagonist (9R\/S)-3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic\nacid 4-fluoro-benzylamide (SHA 68)","volume":"54","author":"Trapella","year":"2011","journal-title":"J. Med.\nChem."},{"key":"2026090122392020200_cit35","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1107\/S0108767383001762","article-title":"On Enantiomorph-Polarity\nEstimation","volume":"A39","author":"Flack","year":"1983","journal-title":"Acta Crystallogr."}],"container-title":["ACS Chemical Neuroscience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/cn500113c","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/acncdm\/article-pdf\/5\/8\/731\/8625411\/cn500113c.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/acncdm\/article-pdf\/5\/8\/731\/8625411\/cn500113c.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T02:40:30Z","timestamp":1788316830000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/acncdm\/article\/5\/8\/731\/830751\/Identification-of-Neuropeptide-S-Antagonists"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,6,25]]},"references-count":36,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2014,6,25]]},"published-print":{"date-parts":[[2014,8,20]]}},"URL":"https:\/\/doi.org\/10.1021\/cn500113c","relation":{},"ISSN":["1948-7193"],"issn-type":[{"value":"1948-7193","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,6,25]]}}}