Peripheralization Strategies Applied to Morphinans and Implications for Improved Treatment of Pain
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 ‘opioid crisis’, warrant consideration on new opioid analgesic discovery strategie...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-06-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/12/4761 |
| _version_ | 1827736225070448640 |
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| author | Helmut Schmidhammer Mahmoud Al-Khrasani Susanna Fürst Mariana Spetea |
| author_facet | Helmut Schmidhammer Mahmoud Al-Khrasani Susanna Fürst Mariana Spetea |
| author_sort | Helmut Schmidhammer |
| collection | DOAJ |
| description | 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 ‘opioid crisis’, 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 <i>N</i>-methylmorphinans to limit their ability to cross the blood–brain 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. |
| first_indexed | 2024-03-11T02:06:43Z |
| format | Article |
| id | doaj.art-e78b265ba0fe4ef5af3c578155bc1697 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-11T02:06:43Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-e78b265ba0fe4ef5af3c578155bc16972023-11-18T11:50:01ZengMDPI AGMolecules1420-30492023-06-012812476110.3390/molecules28124761Peripheralization Strategies Applied to Morphinans and Implications for Improved Treatment of PainHelmut Schmidhammer0Mahmoud Al-Khrasani1Susanna Fürst2Mariana Spetea3Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, AustriaDepartment of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, H-1445 Budapest, HungaryDepartment of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, H-1445 Budapest, HungaryDepartment of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, AustriaOpioids 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 ‘opioid crisis’, 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 <i>N</i>-methylmorphinans to limit their ability to cross the blood–brain 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.https://www.mdpi.com/1420-3049/28/12/4761painanalgesiaopioid receptorsperipheral analgesiaperipherally restricted opioidsmorphine |
| spellingShingle | Helmut Schmidhammer Mahmoud Al-Khrasani Susanna Fürst Mariana Spetea Peripheralization Strategies Applied to Morphinans and Implications for Improved Treatment of Pain Molecules pain analgesia opioid receptors peripheral analgesia peripherally restricted opioids morphine |
| title | Peripheralization Strategies Applied to Morphinans and Implications for Improved Treatment of Pain |
| title_full | Peripheralization Strategies Applied to Morphinans and Implications for Improved Treatment of Pain |
| title_fullStr | Peripheralization Strategies Applied to Morphinans and Implications for Improved Treatment of Pain |
| title_full_unstemmed | Peripheralization Strategies Applied to Morphinans and Implications for Improved Treatment of Pain |
| title_short | Peripheralization Strategies Applied to Morphinans and Implications for Improved Treatment of Pain |
| title_sort | peripheralization strategies applied to morphinans and implications for improved treatment of pain |
| topic | pain analgesia opioid receptors peripheral analgesia peripherally restricted opioids morphine |
| url | https://www.mdpi.com/1420-3049/28/12/4761 |
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