{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T02:48:33Z","timestamp":1788922113209,"version":"build-2803163510"},"reference-count":48,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,10,5]],"date-time":"2025-10-05T00:00:00Z","timestamp":1759622400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["UG3 NS132600"],"award-info":[{"award-number":["UG3 NS132600"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["UH3 NS132600"],"award-info":[{"award-number":["UH3 NS132600"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Medical Research Program","award":["W8lXWH-15-1-0452"],"award-info":[{"award-number":["W8lXWH-15-1-0452"]}]},{"name":"Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Medical Research Program","award":["W8lXWH-15-1-0464"],"award-info":[{"award-number":["W8lXWH-15-1-0464"]}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Molecules"],"abstract":"<jats:p>Kappa opioid receptor (KOR) antagonists may have therapeutic potential to prevent stress-induced relapse in abstinent individuals with cocaine use disorder (CUD). The macrocyclic peptide [D-Trp]CJ-15,208 (cyclo[Phe-D-Pro-Phe-D-Trp]) is an orally bioavailable, brain\u2013penetrant selective KOR antagonist that prevents stress-induced reinstatement of cocaine-seeking behavior in a mouse model of CUD. We synthesized and evaluated analogs of this lead compound with substitutions for the D-Trp residue to identify analogs that exhibit more potent central KOR antagonism following oral administration. The peptides were synthesized by a combination of solid phase and solution peptide synthetic methodologies, and their pharmacological activity was evaluated both in vitro (for KOR affinity, selectivity and antagonism) and in vivo (for antinociception and KOR antagonism), with promising analogs evaluated for their ability to prevent stress-induced reinstatement of cocaine-seeking behavior in the mouse conditioned place preference (CPP) assay. A variety of substituted D-Phe or modified D-Trp derivatives were tolerated by KOR with retention of significant KOR antagonism in vivo after oral administration. Macrocyclic peptide pretreatment, per os, significantly prevented stress-induced reinstatement of cocaine CPP at doses of 10 and 30 mg\/kg of [D-Phe4]CJ-15,208, 4, and 30 mg\/kg of [D-Trp(formamide)]CJ-15,208, 3, which are 6-fold and 2-fold lower, respectively, than that needed for {D-Trp]CJ-15,208.<\/jats:p>","DOI":"10.3390\/molecules30193993","type":"journal-article","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T13:33:41Z","timestamp":1759757621000},"page":"3993","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Optimization of the Macrocyclic Tetrapeptide [D-Trp]CJ-15,208 to Prevent Stress-Induced Relapse of Cocaine-Seeking Behavior"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7954-9850","authenticated-orcid":false,"given":"Jane V.","family":"Aldrich","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitry Y.","family":"Yakovlev","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1005-3355","authenticated-orcid":false,"given":"Jeremy S.","family":"Coleman","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0798-1721","authenticated-orcid":false,"given":"Sanjeewa N.","family":"Senadheera","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, The University of Kansas, Lawrence, KS 66045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather M.","family":"Stacy","sequence":"additional","affiliation":[{"name":"Department of Cellular and Systems Pharmacology, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4995-1410","authenticated-orcid":false,"given":"Shainnel O.","family":"Eans","sequence":"additional","affiliation":[{"name":"Department of Cellular and Systems Pharmacology, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian I.","family":"Knapp","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, College of Medicine, University of Rochester, Rochester, NY 14642, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4305-5111","authenticated-orcid":false,"given":"Jean M.","family":"Bidlack","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, College of Medicine, University of Rochester, Rochester, NY 14642, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9851-9342","authenticated-orcid":false,"given":"Jay P.","family":"McLaughlin","sequence":"additional","affiliation":[{"name":"Department of Cellular and Systems Pharmacology, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,5]]},"reference":[{"key":"ref_1","unstructured":"Estrallado, N. 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