{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,18]],"date-time":"2025-10-18T10:58:06Z","timestamp":1760785086773,"version":"build-2065373602"},"reference-count":92,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2022,8,25]],"date-time":"2022-08-25T00:00:00Z","timestamp":1661385600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000026","name":"NIDA","doi-asserted-by":"publisher","award":["R33DA044425"],"award-info":[{"award-number":["R33DA044425"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The design and development of analgesics with mixed-opioid receptor interactions has been reported to decrease side effects, minimizing respiratory depression and reinforcing properties to generate safer analgesic therapeutics. We synthesized bis-cyclic guanidine heterocyclic peptidomimetics from reduced tripeptides. In vitro screening with radioligand competition binding assays demonstrated variable affinity for the mu-opioid receptor (MOR), delta-opioid receptor (DOR), and kappa-opioid receptor (KOR) across the series, with compound 1968-22 displaying good affinity for all three receptors. Central intracerebroventricular (i.c.v.) administration of 1968-22 produced dose-dependent, opioid receptor-mediated antinociception in the mouse 55 \u00b0C warm-water tail-withdrawal assay, and 1968-22 also produced significant antinociception up to 80 min after oral administration (10 mg\/kg, p.o.). Compound 1968-22 was detected in the brain 5 min after intravenous administration and was shown to be stable in the blood for at least 30 min. Central administration of 1968-22 did not produce significant respiratory depression, locomotor effects or conditioned place preference or aversion. The data suggest these bis-cyclic guanidine heterocyclic peptidomimetics with multifunctional opioid receptor activity may hold potential as new analgesics with fewer liabilities of use.<\/jats:p>","DOI":"10.3390\/ijms23179623","type":"journal-article","created":{"date-parts":[[2022,8,25]],"date-time":"2022-08-25T21:28:12Z","timestamp":1661462892000},"page":"9623","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Bis-Cyclic Guanidine Heterocyclic Peptidomimetics as Opioid Ligands with Mixed \u03bc-, \u03ba- and \u03b4-Opioid Receptor Interactions: A Potential Approach to Novel Analgesics"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9851-9342","authenticated-orcid":false,"given":"Jay P.","family":"McLaughlin","sequence":"first","affiliation":[{"name":"Department of Pharmacodynamics, University of Florida, Gainesville, FL 32610, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ramanjaneyulu","family":"Rayala","sequence":"additional","affiliation":[{"name":"Center for Translational Science, Florida International University, Port St. Lucie, FL 34987, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashley J.","family":"Bunnell","sequence":"additional","affiliation":[{"name":"Center for Translational Science, Florida International University, Port St. Lucie, FL 34987, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9230-7533","authenticated-orcid":false,"given":"Mukund P.","family":"Tantak","sequence":"additional","affiliation":[{"name":"Center for Translational Science, Florida International University, Port St. Lucie, FL 34987, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shainnel O.","family":"Eans","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, University of Florida, Gainesville, FL 32610, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Khadija","family":"Nefzi","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, University of Florida, Gainesville, FL 32610, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle L.","family":"Ganno","sequence":"additional","affiliation":[{"name":"Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Colette T.","family":"Dooley","sequence":"additional","affiliation":[{"name":"Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adel","family":"Nefzi","sequence":"additional","affiliation":[{"name":"Center for Translational Science, Florida International University, Port St. Lucie, FL 34987, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S24","DOI":"10.1097\/j.pain.0000000000001270","article-title":"The brain on opioids","volume":"159","author":"Ballantyne","year":"2018","journal-title":"Pain"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1038\/s41380-020-0661-4","article-title":"The changing opioid crisis: Development, challenges and opportunities","volume":"26","author":"Volkow","year":"2021","journal-title":"Mol. 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