{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T01:34:14Z","timestamp":1772760854601,"version":"3.50.1"},"reference-count":66,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T00:00:00Z","timestamp":1693267200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institute on Drug Abuse","doi-asserted-by":"publisher","award":["R01 DA032928"],"award-info":[{"award-number":["R01 DA032928"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institute on Drug Abuse","doi-asserted-by":"publisher","award":["UG3 NS132600"],"award-info":[{"award-number":["UG3 NS132600"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institute on Drug Abuse","doi-asserted-by":"publisher","award":["W8lXWH-15-1-0452"],"award-info":[{"award-number":["W8lXWH-15-1-0452"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institute on Drug Abuse","doi-asserted-by":"publisher","award":["W8lXWH-15-1-0464"],"award-info":[{"award-number":["W8lXWH-15-1-0464"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"Office of the Assistant Secretary of Defense for Health Affairs","doi-asserted-by":"publisher","award":["R01 DA032928"],"award-info":[{"award-number":["R01 DA032928"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"Office of the Assistant Secretary of Defense for Health Affairs","doi-asserted-by":"publisher","award":["UG3 NS132600"],"award-info":[{"award-number":["UG3 NS132600"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"Office of the Assistant Secretary of Defense for Health Affairs","doi-asserted-by":"publisher","award":["W8lXWH-15-1-0452"],"award-info":[{"award-number":["W8lXWH-15-1-0452"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"Office of the Assistant Secretary of Defense for Health Affairs","doi-asserted-by":"publisher","award":["W8lXWH-15-1-0464"],"award-info":[{"award-number":["W8lXWH-15-1-0464"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>The macrocyclic tetrapeptide CJ-15,208 (cyclo[Phe-D-Pro-Phe-Trp]) and its D-Trp isomer exhibit kappa opioid receptor (KOR) antagonism which prevents stress-induced reinstatement of extinguished cocaine-conditioned place preference. Here, we evaluated the effects of substitution of Trp and D-Trp on the peptides\u2019 opioid activity, antinociceptive tolerance, and the ability to prevent relapse to extinguished drug-CPP. Six analogs were synthesized using a combination of solid-phase peptide synthesis and cyclization in solution. The analogs were evaluated in vitro for opioid receptor affinity in radioligand competition binding assays, efficacy in the [35S]GTP\u03b3S assay, metabolic stability in mouse liver microsomes, and for opioid activity and selectivity in vivo in the mouse 55 \u00b0C warm-water tail-withdrawal assay. Potential liabilities of locomotor impairment, respiratory depression, acute tolerance, and conditioned place preference (CPP) were also assessed in vivo, and the ameliorating effect of analogs on the reinstatement of extinguished cocaine-place preference was assessed. Substitutions of other D-amino acids for D-Trp did not affect (or in one case increased) KOR affinity, while two of the three substitutions of an L-amino acid for Trp decreased KOR affinity. In contrast, all but one substitution increased mu opioid receptor (MOR) affinity in vitro. The metabolic stabilities of the analogs were similar to those of their respective parent peptides, with analogs containing a D-amino acid being much more rapidly metabolized than those containing an L-amino acid in this position. In vivo, CJ-15,208 analogs demonstrated antinociception, although potencies varied over an 80-fold range and the mediating opioid receptors differed by substitution. KOR antagonism was lost for all but the D-benzothienylalanine analog, and the 2\u2032-naphthylalanine analog instead demonstrated significant delta opioid receptor (DOR) antagonism. Introduction of DOR antagonism coincided with reduced acute opioid antinociceptive tolerance and prevented stress-induced reinstatement of extinguished cocaine-CPP.<\/jats:p>","DOI":"10.3390\/ph16091218","type":"journal-article","created":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T08:26:52Z","timestamp":1693297612000},"page":"1218","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Tryptophan Substitution in CJ-15,208 (cyclo[Phe-D-Pro-Phe-Trp]) Introduces \u03b4-Opioid Receptor Antagonism, Preventing Antinociceptive Tolerance and Stress-Induced Reinstatement of Extinguished Cocaine-Conditioned Place Preference"],"prefix":"10.3390","volume":"16","author":[{"given":"Kristen H.","family":"Scherrer","sequence":"first","affiliation":[{"name":"Department of Pharmacodynamics, The University of Florida, Gainesville, FL 32610, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shainnel O.","family":"Eans","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, The University of Florida, Gainesville, FL 32610, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica M.","family":"Medina","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, The University of Florida, Gainesville, FL 32610, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tanvir","family":"Khaliq","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, The University of Kansas, Lawrence, KS 66045, USA"},{"name":"Department of Medicinal Chemistry, The University of Florida, Gainesville, FL 32610, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8521-4507","authenticated-orcid":false,"given":"Thomas F.","family":"Murray","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Neuroscience, Creighton University School of Medicine, Omaha, NE 68178, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9851-9342","authenticated-orcid":false,"given":"Jay P.","family":"McLaughlin","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, The University of Florida, Gainesville, FL 32610, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7954-9850","authenticated-orcid":false,"given":"Jane V.","family":"Aldrich","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, The University of Kansas, Lawrence, KS 66045, USA"},{"name":"Department of Medicinal Chemistry, The University of Florida, Gainesville, FL 32610, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1151\/ascp08424","article-title":"Challenges in using opioids to treat pain in persons with substance use disorders","volume":"4","author":"Savage","year":"2008","journal-title":"Addict. 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