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Ministry of Human Capacities in Hungary, within the framework of the Neurology Thematic Programme of Semmelweis University","award":["P21350"],"award-info":[{"award-number":["P21350"]}]},{"name":"University of Innsbruck, and the Higher Education Institutional Excellence Programme of the Ministry of Human Capacities in Hungary, within the framework of the Neurology Thematic Programme of Semmelweis University","award":["TRP16-18"],"award-info":[{"award-number":["TRP16-18"]}]},{"name":"University of Innsbruck, and the Higher Education Institutional Excellence Programme of the Ministry of Human Capacities in Hungary, within the framework of the Neurology Thematic Programme of Semmelweis University","award":["TRP19-B18"],"award-info":[{"award-number":["TRP19-B18"]}]},{"name":"University of Innsbruck, and the Higher Education Institutional Excellence Programme of the Ministry of Human Capacities in Hungary, within the framework of the Neurology Thematic Programme of Semmelweis University","award":["I4697"],"award-info":[{"award-number":["I4697"]}]},{"name":"University of Innsbruck, and the Higher Education Institutional Excellence Programme of the Ministry of Human Capacities in Hungary, within the framework of the Neurology Thematic Programme of Semmelweis University","award":["TWF-UNI-0404\/949"],"award-info":[{"award-number":["TWF-UNI-0404\/949"]}]},{"name":"University of Innsbruck, and the Higher Education Institutional Excellence Programme of the Ministry of Human Capacities in Hungary, within the framework of the Neurology Thematic Programme of Semmelweis University","award":["TKP 2021 EGA-25"],"award-info":[{"award-number":["TKP 2021 EGA-25"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Opioids are considered the most effective analgesics for the treatment of moderate to severe acute and chronic pain. However, the inadequate benefit\/risk ratio of currently available opioids, together with the current \u2018opioid crisis\u2019, warrant consideration on new opioid analgesic discovery strategies. Targeting peripheral opioid receptors as effective means of treating pain and avoiding the centrally mediated side effects represents a research area of substantial and continuous attention. Among clinically used analgesics, opioids from the class of morphinans (i.e., morphine and structurally related analogues) are of utmost clinical importance as analgesic drugs activating the mu-opioid receptor. In this review, we focus on peripheralization strategies applied to N-methylmorphinans to limit their ability to cross the blood\u2013brain barrier, thus minimizing central exposure and the associated undesired side effects. Chemical modifications to the morphinan scaffold to increase hydrophilicity of known and new opioids, and nanocarrier-based approaches to selectively deliver opioids, such as morphine, to the peripheral tissue are discussed. The preclinical and clinical research activities have allowed for the characterization of a variety of compounds that show low central nervous system penetration, and therefore an improved side effect profile, yet maintaining the desired opioid-related antinociceptive activity. Such peripheral opioid analgesics may represent alternatives to presently available drugs for an efficient and safer pain therapy.<\/jats:p>","DOI":"10.3390\/molecules28124761","type":"journal-article","created":{"date-parts":[[2023,6,15]],"date-time":"2023-06-15T02:03:19Z","timestamp":1686794599000},"page":"4761","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Peripheralization Strategies Applied to Morphinans and Implications for Improved Treatment of Pain"],"prefix":"10.3390","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8752-5050","authenticated-orcid":false,"given":"Helmut","family":"Schmidhammer","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8488-3266","authenticated-orcid":false,"given":"Mahmoud","family":"Al-Khrasani","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyv\u00e1rad t\u00e9r 4, H-1445 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanna","family":"F\u00fcrst","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyv\u00e1rad t\u00e9r 4, H-1445 Budapest, Hungary"}],"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 (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1146\/annurev-neuro-080317-061522","article-title":"Endogenous and exogenous opioids in pain","volume":"41","author":"Corder","year":"2018","journal-title":"Annu. 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