{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T15:06:03Z","timestamp":1772118363661,"version":"3.50.1"},"reference-count":30,"publisher":"Wiley","issue":"15","license":[{"start":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T00:00:00Z","timestamp":1750982400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01NS119266"],"award-info":[{"award-number":["R01NS119266"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2025,8,2]]},"abstract":"<jats:p>\n                    The discovery and characterization of a novel series of 4,4\u2010difluoropiperidine ether\u2010based dopamine D4 receptor antagonists are reported. Structure\u2013activity relationship studies lead to the identification of compound 14a, which displays exceptional binding affinity for the D4 receptor (Ki\u2009=\u20090.3\u2009n\n                    <jats:sc>m<\/jats:sc>\n                    ) and remarkable selectivity over other dopamine receptor subtypes (&gt;2000\u2010fold vs. D1, D2, D3, and D5). However, compounds in this series are shown to have poor microsomal stability and high plasma protein binding. Despite these limitations, the exceptional selectivity profile of these compounds makes them valuable tool compounds for investigating the D4 receptor signaling in cellular models of L\u2010DOPA\u2010induced dyskinesias. These findings provide important structural insights into the future development of metabolically stable D4 receptor antagonists for therapeutic applications.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.202500298","type":"journal-article","created":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T14:38:25Z","timestamp":1748529505000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Synthesis and Biological Characterization of 4,4\u2010Difluoro\u20103\u2010(phenoxymethyl)piperidine Scaffold as Dopamine 4 Receptor (D\n                    <sub>4<\/sub>\n                    R) Antagonist in\u2009vitro Tool compounds"],"prefix":"10.1002","volume":"20","author":[{"given":"Saeedeh","family":"Saeedi","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences College of Pharmacy University of Nebraska Medical Center  Omaha NE 68198 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sumaiya","family":"Nahid","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences College of Pharmacy University of Nebraska Medical Center  Omaha NE 68198 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anish K.","family":"Vadukoot","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences College of Pharmacy University of Nebraska Medical Center  Omaha NE 68198 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4958-1697","authenticated-orcid":false,"given":"Corey R.","family":"Hopkins","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences College of Pharmacy University of Nebraska Medical Center  Omaha NE 68198 USA"},{"name":"UNMC Center for Drug Design and Innovation College of Pharmacy University of Nebraska Medical Center  Omaha NE 68198 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,6,27]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00702-018-1900-6"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1159\/000300647"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.27959"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.0022-3042.2001.00702.x"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1460-9568.1998.00056.x"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(98)00633-2"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.parkreldis.2008.11.001"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(94)00782-3"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-2999(00)00310-1"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2016.09.001"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.112.195693"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1097\/FBP.0000000000000096"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.7b00151"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2016.03.102"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2022.128615"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2016.10.049"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo960057x"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11691"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.8b00077"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/cn100008c"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/cn100007x"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aan5468"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-0917-9"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.48822"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm0306430"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm030644s"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0090-9556(24)14938-0"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3565(24)36999-X"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1021\/ml900012h"},{"key":"e_1_2_7_31_1","unstructured":"https:\/\/chemaxon.okta.com\/oauth2\/aus3qkblpwzIDQBJF417\/v1\/authorize?response_type=code&client_id=0oa54wn8x4lRdqiOZ417&scope=openid%20email%20profile&state=vaRf2e_SK1vksC1utor546MXL8ALxk7K0PloiYh59SQ%3D&redirect_uri=https:\/\/chemicalize.com\/login\/oauth2\/code\/okta&nonce=3Q7wl0tar5OS8svia6cRqT_Chb5wl3bjBQOylcX06Ro."}],"container-title":["ChemMedChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.202500298","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T16:30:01Z","timestamp":1760286601000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cmdc.202500298"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,27]]},"references-count":30,"journal-issue":{"issue":"15","published-print":{"date-parts":[[2025,8,2]]}},"alternative-id":["10.1002\/cmdc.202500298"],"URL":"https:\/\/doi.org\/10.1002\/cmdc.202500298","archive":["Portico"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.26434\/chemrxiv-2025-g6zh3","asserted-by":"object"}]},"ISSN":["1860-7179","1860-7187"],"issn-type":[{"value":"1860-7179","type":"print"},{"value":"1860-7187","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,27]]},"assertion":[{"value":"2025-04-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-27","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e202500298"}}