{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:11:28Z","timestamp":1790813488476,"version":"4.1.0"},"reference-count":83,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2024,4,3]],"date-time":"2024-04-03T00:00:00Z","timestamp":1712102400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["I2463-B21"],"award-info":[{"award-number":["I2463-B21"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["I4697"],"award-info":[{"award-number":["I4697"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University of Innsbruck","award":["I2463-B21"],"award-info":[{"award-number":["I2463-B21"]}]},{"name":"University of Innsbruck","award":["I4697"],"award-info":[{"award-number":["I4697"]}]},{"name":"Austrian Science Fund (FWF)","award":["I2463-B21"],"award-info":[{"award-number":["I2463-B21"]}]},{"name":"Austrian Science Fund (FWF)","award":["I4697"],"award-info":[{"award-number":["I4697"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Diverse chemical and pharmacological strategies are currently being explored to minimize the unwanted side effects of currently used opioid analgesics while achieving effective pain relief. The use of multitarget ligands with activity at more than one receptor represents a promising therapeutic approach. We recently reported a bifunctional peptide-based hybrid LENART01 combining dermorphin and ranatensin pharmacophores, which displays activity to the mu-opioid receptor (MOR) and dopamine D2 receptor (D2R) in rat brains and spinal cords. In this study, we investigated the in vitro binding and functional activities to the human MOR and the in vivo pharmacology of LENART01 in mice after subcutaneous administration. In vitro binding assays showed LENART01 to bind and be selective to the human MOR over the other opioid receptor subtypes and delta, kappa and nociceptin receptors. In the [35S]GTP\u03b3S binding assay, LENART01 acted as a potent and full agonist to the human MOR. In mice, LENART01 produced dose-dependent antinociceptive effects in formalin-induced inflammatory pain, with increased potency than morphine. Antinociceptive effects were reversed by naloxone, indicating MOR activation in vivo. Behavioral studies also demonstrated LENART01\u2019s properties to induce less adverse effects without locomotor dysfunction and withdrawal syndrome compared to conventional opioid analgesics, such as morphine. LENART01 is the first peptide-based MOR-D2R ligand known to date and the first dual MOR-dopamine D2R ligand for which in vivo pharmacology is reported with antinociceptive efficacy and reduced opioid-related side effects. Our current findings may pave the way to new pain therapeutics with limited side effects in acute and chronic use.<\/jats:p>","DOI":"10.3390\/ijms25074007","type":"journal-article","created":{"date-parts":[[2024,4,3]],"date-time":"2024-04-03T11:01:41Z","timestamp":1712142101000},"page":"4007","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["In Vitro and In Vivo Pharmacological Profiles of LENART01, a Dermorphin\u2013Ranatensin Hybrid Peptide"],"prefix":"10.3390","volume":"25","author":[{"given":"Nadine","family":"Hochrainer","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pawel","family":"Serafin","sequence":"additional","affiliation":[{"name":"Military Institute of Hygiene and Epidemiology, 01-163 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"D\u2019Ingiullo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University \u201cG. d\u2019Annunzio\u201d of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7242-4860","authenticated-orcid":false,"given":"Adriano","family":"Mollica","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University \u201cG. d\u2019Annunzio\u201d of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1876-1321","authenticated-orcid":false,"given":"Sebastian","family":"Granica","sequence":"additional","affiliation":[{"name":"Microbiota Lab, Department of Pharmacognosy and Molecular Basis of Phytotherapy, Medical University of Warsaw, 02-097 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2045-198X","authenticated-orcid":false,"given":"Marek","family":"Brytan","sequence":"additional","affiliation":[{"name":"Military Institute of Hygiene and Epidemiology, 01-163 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8389-0920","authenticated-orcid":false,"given":"Patrycja","family":"Kleczkowska","sequence":"additional","affiliation":[{"name":"Maria Sklodowska-Curie Medical Academy in Warsaw, 03-411 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2379-5358","authenticated-orcid":false,"given":"Mariana","family":"Spetea","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,3]]},"reference":[{"key":"ref_1","first-page":"287","article-title":"Survey of chronic pain in Europe: Prevalence, impact on daily life, and treatment","volume":"10","author":"Breivik","year":"2006","journal-title":"Pain"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1016\/j.clinbiochem.2014.05.065","article-title":"Pharmacogenetics of chronic pain management","volume":"47","author":"Kapur","year":"2014","journal-title":"Clin. 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