{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T05:06:12Z","timestamp":1780549572699,"version":"3.54.1"},"reference-count":47,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2020,9,17]],"date-time":"2020-09-17T00:00:00Z","timestamp":1600300800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The National Science Center (Poland)","award":["2015\/17\/B\/ST5\/00153"],"award-info":[{"award-number":["2015\/17\/B\/ST5\/00153"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The opioid receptors are members of the G-protein-coupled receptor (GPCR) family and are known to modulate a variety of biological functions, including pain perception. Despite considerable advances, the mechanisms by which opioid agonists and antagonists interact with their receptors and exert their effect are still not completely understood. In this report, six new hybrids of the Dmt-Tic pharmacophore and cyclic peptides, which were shown before to have a high affinity for the \u00b5-opioid receptor (MOR) were synthesized and characterized pharmacologically in calcium mobilization functional assays. All obtained ligands turned out to be selective antagonists of the \u03b4-opioid receptor (DOR) and did not activate or block the MOR. The three-dimensional structural determinants responsible for the DOR antagonist properties of these analogs were further investigated by docking studies. The results indicate that these compounds attach to the DOR in a slightly different orientation with respect to the Dmt-Tic pharmacophore than Dmt-Tic\u03a8[CH2-NH]Phe-Phe-NH2 (DIPP-NH2[\u03a8]), a prototypical DOR antagonist peptide. Key pharmacophoric contacts between the DOR and the ligands were maintained through an analogous spatial arrangement of pharmacophores, which could provide an explanation for the predicted high-affinity binding and the experimentally observed functional properties of the novel synthetic ligands.<\/jats:p>","DOI":"10.3390\/molecules25184260","type":"journal-article","created":{"date-parts":[[2020,9,18]],"date-time":"2020-09-18T10:22:23Z","timestamp":1600424543000},"page":"4260","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Design, Synthesis and Functional Analysis of Cyclic Opioid Peptides with Dmt-Tic Pharmacophore"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3447-1295","authenticated-orcid":false,"given":"Arijit","family":"Sarkar","sequence":"first","affiliation":[{"name":"Laboratory of Chemical Biology, Institute of Biochemistry, Biological Research Centre, Szeged, 62. Temesv\u00e1ri krt., H-6726 Szeged, Hungary"},{"name":"Theoretical Medicine Doctoral School, Faculty of Medicine, University of Szeged, 97. Tisza L. krt., H-6722 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Adamska-Bartlomiejczyk","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6\/8, 92-215 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justyna","family":"Piekielna-Ciesielska","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6\/8, 92-215 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karol","family":"Wtorek","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6\/8, 92-215 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2943-2782","authenticated-orcid":false,"given":"Alicja","family":"Kluczyk","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, University of Wroclaw, F. Joliot-Curie 14, 50-383 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6331-3536","authenticated-orcid":false,"given":"Attila","family":"Borics","sequence":"additional","affiliation":[{"name":"Laboratory of Chemical Biology, Institute of Biochemistry, Biological Research Centre, Szeged, 62. Temesv\u00e1ri krt., H-6726 Szeged, Hungary"},{"name":"Theoretical Medicine Doctoral School, Faculty of Medicine, University of Szeged, 97. Tisza L. krt., H-6722 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Janecka","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6\/8, 92-215 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1146\/annurev.biochem.73.011303.073940","article-title":"Opioid receptors","volume":"73","author":"Waldhoer","year":"2004","journal-title":"Annu. Rev. Biochem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1007\/s11064-018-2542-7","article-title":"The Peripheral versus central antinociception of a novel opioid agonist: Acute inflammatory pain in rats","volume":"43","author":"Balogh","year":"2018","journal-title":"Neurochem. 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