{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:31:08Z","timestamp":1786977068440,"version":"build-2736575974"},"reference-count":45,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2023,7,14]],"date-time":"2023-07-14T00:00:00Z","timestamp":1689292800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Archiv der Pharmazie"],"published-print":{"date-parts":[[2023,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The increasing misuse of novel synthetic opioids (NSOs) represents a serious public health concern. In this regard, U\u201047700 (\n                    <jats:italic>trans<\/jats:italic>\n                    \u20103,4\u2010dichloro\u2010\n                    <jats:italic>N<\/jats:italic>\n                    \u2010[2\u2010(dimethylamino)cyclohexyl]\u2010\n                    <jats:italic>N<\/jats:italic>\n                    \u2010methylbenzamide) and related \u201cU\u2010compounds\u201d emerged on recreational drug markets as synthetic substitutes for illicit heroin and constituents of counterfeit pain medications. While the pharmacology of U\u2010compounds has been investigated using in vitro and in vivo methods, there is still a lack of understanding about the details of ligand\u2013receptor interactions at the molecular level. To this end, we have developed a molecular modeling protocol based on docking and molecular dynamics simulations to assess the nature of ligand\u2013receptor interactions for U\u201047700,\n                    <jats:italic>N,N<\/jats:italic>\n                    \u2010didesmethyl U\u201047700, and U\u201050488 at the mu\u2010opioid receptor (MOR) and kappa\u2010opioid receptor (KOR). The evaluation of ligand\u2013receptor and ligand\u2013receptor\u2010membrane interaction energies enabled the identification of subtle conformational shifts in the receptors induced by ligand binding. Interestingly, the removal of two key methyl groups from U\u201047700, to form\n                    <jats:italic>N,N<\/jats:italic>\n                    \u2010didesmethyl U\u201047700, caused a loss of hydrogen bond contact with tryptophan (Trp)229, which may underlie the lower interaction energy and reduced MOR affinity for the compound. Taken together, our results are consistent with the reported biological findings for U\u2010compounds and provide a molecular basis for the MOR selectivity of U\u201047700 and KOR selectivity of U\u201050488.\n                  <\/jats:p>","DOI":"10.1002\/ardp.202300256","type":"journal-article","created":{"date-parts":[[2023,7,14]],"date-time":"2023-07-14T23:14:55Z","timestamp":1689376495000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["In silico characterization of ligand\u2013receptor interactions for U\u201047700,\n                    <i>N,N<\/i>\n                    \u2010didesmethyl\u2010U\u201047700, U\u201050488 at mu\u2010 and kappa\u2010opioid receptors"],"prefix":"10.1002","volume":"356","author":[{"given":"Antonio","family":"Laus","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences University of Cagliari, Cittadella Universitaria di Monserrato Cagliari Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2547-0071","authenticated-orcid":false,"given":"Amit","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Electrical and Electronic Engineering University of Cagliari Cagliari Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierluigi","family":"Caboni","sequence":"additional","affiliation":[{"name":"Department of Life and Environmental Sciences University of Cagliari, Cittadella Universitaria di Monserrato Cagliari Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria A.","family":"De Luca","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences University of Cagliari, Cittadella Universitaria di Monserrato Cagliari Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael H.","family":"Baumann","sequence":"additional","affiliation":[{"name":"Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse National Institutes of Health Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrico","family":"Pieroni","sequence":"additional","affiliation":[{"name":"CRS4, Modelling, Simulation and Data Analysis Program Pula Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0081-5704","authenticated-orcid":false,"given":"Graziella","family":"Tocco","sequence":"additional","affiliation":[{"name":"Department of Life and Environmental Sciences University of Cagliari, Cittadella Universitaria di Monserrato Cagliari Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,7,14]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.73.011303.073940"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/brainsci10110895"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11419-018-0454-5"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2017.10.016"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2011.06199.x"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0278-5846(82)80130-9"},{"issue":"1","key":"e_1_2_8_8_1","first-page":"7","volume":"224","author":"Von Voigtlander P. 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