Biased versus Partial Agonism in the Search for Safer Opioid Analgesics
Opioids such as morphine—acting at the mu opioid receptor—are the mainstay for treatment of moderate to severe pain and have good efficacy in these indications. However, these drugs produce a plethora of unwanted adverse effects including respiratory depression, constipation, immune suppression and...
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| Format: | Article |
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MDPI AG
2020-08-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/17/3870 |
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| author | Joaquim Azevedo Neto Anna Costanzini Roberto De Giorgio David G. Lambert Chiara Ruzza Girolamo Calò |
| author_facet | Joaquim Azevedo Neto Anna Costanzini Roberto De Giorgio David G. Lambert Chiara Ruzza Girolamo Calò |
| author_sort | Joaquim Azevedo Neto |
| collection | DOAJ |
| description | Opioids such as morphine—acting at the mu opioid receptor—are the mainstay for treatment of moderate to severe pain and have good efficacy in these indications. However, these drugs produce a plethora of unwanted adverse effects including respiratory depression, constipation, immune suppression and with prolonged treatment, tolerance, dependence and abuse liability. Studies in β-arrestin 2 gene knockout (βarr2(−/−)) animals indicate that morphine analgesia is potentiated while side effects are reduced, suggesting that drugs biased away from arrestin may manifest with a reduced-side-effect profile. However, there is controversy in this area with improvement of morphine-induced constipation and reduced respiratory effects in βarr2(−/−) mice. Moreover, studies performed with mice genetically engineered with G-protein-biased mu receptors suggested increased sensitivity of these animals to both analgesic actions and side effects of opioid drugs. Several new molecules have been identified as mu receptor G-protein-biased agonists, including oliceridine (TRV130), PZM21 and SR–17018. These compounds have provided preclinical data with apparent support for bias toward G proteins and the genetic premise of effective and safer analgesics. There are clinical data for oliceridine that have been very recently approved for short term intravenous use in hospitals and other controlled settings. While these data are compelling and provide a potential new pathway-based target for drug discovery, a simpler explanation for the behavior of these biased agonists revolves around differences in intrinsic activity. A highly detailed study comparing oliceridine, PZM21 and SR–17018 (among others) in a range of assays showed that these molecules behave as partial agonists. Moreover, there was a correlation between their therapeutic indices and their efficacies, but not their bias factors. If there is amplification of G-protein, but not arrestin pathways, then agonists with reduced efficacy would show high levels of activity at G-protein and low or absent activity at arrestin; offering analgesia with reduced side effects or ‘apparent bias’. Overall, the current data suggests—and we support—caution in ascribing biased agonism to reduced-side-effect profiles for mu-agonist analgesics. |
| first_indexed | 2024-03-10T16:50:06Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T16:50:06Z |
| publishDate | 2020-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-c2d177aea22a4257af176aa2c994171b2023-11-20T11:21:09ZengMDPI AGMolecules1420-30492020-08-012517387010.3390/molecules25173870Biased versus Partial Agonism in the Search for Safer Opioid AnalgesicsJoaquim Azevedo Neto0Anna Costanzini1Roberto De Giorgio2David G. Lambert3Chiara Ruzza4Girolamo Calò5Department of Biomedical and Specialty Surgical Sciences, Section of Pharmacology, University of Ferrara, 44121 Ferrara, ItalyDepartment of Morphology, Surgery, Experimental Medicine, University of Ferrara, 44121 Ferrara, ItalyDepartment of Morphology, Surgery, Experimental Medicine, University of Ferrara, 44121 Ferrara, ItalyDepartment of Cardiovascular Sciences, Anesthesia, Critical Care and Pain Management, University of Leicester, Leicester LE1 7RH, UKDepartment of Biomedical and Specialty Surgical Sciences, Section of Pharmacology, University of Ferrara, 44121 Ferrara, ItalyDepartment of Biomedical and Specialty Surgical Sciences, Section of Pharmacology, University of Ferrara, 44121 Ferrara, ItalyOpioids such as morphine—acting at the mu opioid receptor—are the mainstay for treatment of moderate to severe pain and have good efficacy in these indications. However, these drugs produce a plethora of unwanted adverse effects including respiratory depression, constipation, immune suppression and with prolonged treatment, tolerance, dependence and abuse liability. Studies in β-arrestin 2 gene knockout (βarr2(−/−)) animals indicate that morphine analgesia is potentiated while side effects are reduced, suggesting that drugs biased away from arrestin may manifest with a reduced-side-effect profile. However, there is controversy in this area with improvement of morphine-induced constipation and reduced respiratory effects in βarr2(−/−) mice. Moreover, studies performed with mice genetically engineered with G-protein-biased mu receptors suggested increased sensitivity of these animals to both analgesic actions and side effects of opioid drugs. Several new molecules have been identified as mu receptor G-protein-biased agonists, including oliceridine (TRV130), PZM21 and SR–17018. These compounds have provided preclinical data with apparent support for bias toward G proteins and the genetic premise of effective and safer analgesics. There are clinical data for oliceridine that have been very recently approved for short term intravenous use in hospitals and other controlled settings. While these data are compelling and provide a potential new pathway-based target for drug discovery, a simpler explanation for the behavior of these biased agonists revolves around differences in intrinsic activity. A highly detailed study comparing oliceridine, PZM21 and SR–17018 (among others) in a range of assays showed that these molecules behave as partial agonists. Moreover, there was a correlation between their therapeutic indices and their efficacies, but not their bias factors. If there is amplification of G-protein, but not arrestin pathways, then agonists with reduced efficacy would show high levels of activity at G-protein and low or absent activity at arrestin; offering analgesia with reduced side effects or ‘apparent bias’. Overall, the current data suggests—and we support—caution in ascribing biased agonism to reduced-side-effect profiles for mu-agonist analgesics.https://www.mdpi.com/1420-3049/25/17/3870opioidsmu receptoranalgesiaopioid side effectsbiased agonismpartial agonism |
| spellingShingle | Joaquim Azevedo Neto Anna Costanzini Roberto De Giorgio David G. Lambert Chiara Ruzza Girolamo Calò Biased versus Partial Agonism in the Search for Safer Opioid Analgesics Molecules opioids mu receptor analgesia opioid side effects biased agonism partial agonism |
| title | Biased versus Partial Agonism in the Search for Safer Opioid Analgesics |
| title_full | Biased versus Partial Agonism in the Search for Safer Opioid Analgesics |
| title_fullStr | Biased versus Partial Agonism in the Search for Safer Opioid Analgesics |
| title_full_unstemmed | Biased versus Partial Agonism in the Search for Safer Opioid Analgesics |
| title_short | Biased versus Partial Agonism in the Search for Safer Opioid Analgesics |
| title_sort | biased versus partial agonism in the search for safer opioid analgesics |
| topic | opioids mu receptor analgesia opioid side effects biased agonism partial agonism |
| url | https://www.mdpi.com/1420-3049/25/17/3870 |
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