Biased Opioid Ligands
Achieving effective pain management is one of the major challenges associated with modern day medicine. Opioids, such as morphine, have been the reference treatment for moderate to severe acute pain not excluding chronic pain modalities. Opioids act through the opioid receptors, the family of G-prot...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-09-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/18/4257 |
| _version_ | 1797553547659706368 |
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| author | Abdelfattah Faouzi Balazs R. Varga Susruta Majumdar |
| author_facet | Abdelfattah Faouzi Balazs R. Varga Susruta Majumdar |
| author_sort | Abdelfattah Faouzi |
| collection | DOAJ |
| description | Achieving effective pain management is one of the major challenges associated with modern day medicine. Opioids, such as morphine, have been the reference treatment for moderate to severe acute pain not excluding chronic pain modalities. Opioids act through the opioid receptors, the family of G-protein coupled receptors (GPCRs) that mediate pain relief through both the central and peripheral nervous systems. Four types of opioid receptors have been described, including the μ-opioid receptor (MOR), κ-opioid receptor (KOR), δ-opioid receptor (DOR), and the nociceptin opioid peptide receptor (NOP receptor). Despite the proven success of opioids in treating pain, there are still some inherent limitations. All clinically approved MOR analgesics are associated with adverse effects, which include tolerance, dependence, addiction, constipation, and respiratory depression. On the other hand, KOR selective analgesics have found limited clinical utility because they cause sedation, anxiety, dysphoria, and hallucinations. DOR agonists have also been investigated but they have a tendency to cause convulsions. Ligands targeting NOP receptor have been reported in the preclinical literature to be useful as spinal analgesics and as entities against substance abuse disorders while mixed MOR/NOP receptor agonists are useful as analgesics. Ultimately, the goal of opioid-related drug development has always been to design and synthesize derivatives that are equally or more potent than morphine but most importantly are devoid of the dangerous residual side effects and abuse potential. One proposed strategy is to take advantage of biased agonism, in which distinct downstream pathways can be activated by different molecules working through the exact same receptor. It has been proposed that ligands not recruiting β-arrestin 2 or showing a preference for activating a specific G-protein mediated signal transduction pathway will function as safer analgesic across all opioid subtypes. This review will focus on the design and the pharmacological outcomes of biased ligands at the opioid receptors, aiming at achieving functional selectivity. |
| first_indexed | 2024-03-10T16:17:06Z |
| format | Article |
| id | doaj.art-defe553596a944b48ee38b67c14f5567 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T16:17:06Z |
| publishDate | 2020-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-defe553596a944b48ee38b67c14f55672023-11-20T13:59:11ZengMDPI AGMolecules1420-30492020-09-012518425710.3390/molecules25184257Biased Opioid LigandsAbdelfattah Faouzi0Balazs R. Varga1Susruta Majumdar2Center for Clinical Pharmacology, St. Louis College of Pharmacy and Washington University School of Medicine, St. Louis, MO 63131, USACenter for Clinical Pharmacology, St. Louis College of Pharmacy and Washington University School of Medicine, St. Louis, MO 63131, USACenter for Clinical Pharmacology, St. Louis College of Pharmacy and Washington University School of Medicine, St. Louis, MO 63131, USAAchieving effective pain management is one of the major challenges associated with modern day medicine. Opioids, such as morphine, have been the reference treatment for moderate to severe acute pain not excluding chronic pain modalities. Opioids act through the opioid receptors, the family of G-protein coupled receptors (GPCRs) that mediate pain relief through both the central and peripheral nervous systems. Four types of opioid receptors have been described, including the μ-opioid receptor (MOR), κ-opioid receptor (KOR), δ-opioid receptor (DOR), and the nociceptin opioid peptide receptor (NOP receptor). Despite the proven success of opioids in treating pain, there are still some inherent limitations. All clinically approved MOR analgesics are associated with adverse effects, which include tolerance, dependence, addiction, constipation, and respiratory depression. On the other hand, KOR selective analgesics have found limited clinical utility because they cause sedation, anxiety, dysphoria, and hallucinations. DOR agonists have also been investigated but they have a tendency to cause convulsions. Ligands targeting NOP receptor have been reported in the preclinical literature to be useful as spinal analgesics and as entities against substance abuse disorders while mixed MOR/NOP receptor agonists are useful as analgesics. Ultimately, the goal of opioid-related drug development has always been to design and synthesize derivatives that are equally or more potent than morphine but most importantly are devoid of the dangerous residual side effects and abuse potential. One proposed strategy is to take advantage of biased agonism, in which distinct downstream pathways can be activated by different molecules working through the exact same receptor. It has been proposed that ligands not recruiting β-arrestin 2 or showing a preference for activating a specific G-protein mediated signal transduction pathway will function as safer analgesic across all opioid subtypes. This review will focus on the design and the pharmacological outcomes of biased ligands at the opioid receptors, aiming at achieving functional selectivity.https://www.mdpi.com/1420-3049/25/18/4257G-protein biasarrestin recruitmentopioid receptorsrespirationmitragynineanalgesia |
| spellingShingle | Abdelfattah Faouzi Balazs R. Varga Susruta Majumdar Biased Opioid Ligands Molecules G-protein bias arrestin recruitment opioid receptors respiration mitragynine analgesia |
| title | Biased Opioid Ligands |
| title_full | Biased Opioid Ligands |
| title_fullStr | Biased Opioid Ligands |
| title_full_unstemmed | Biased Opioid Ligands |
| title_short | Biased Opioid Ligands |
| title_sort | biased opioid ligands |
| topic | G-protein bias arrestin recruitment opioid receptors respiration mitragynine analgesia |
| url | https://www.mdpi.com/1420-3049/25/18/4257 |
| work_keys_str_mv | AT abdelfattahfaouzi biasedopioidligands AT balazsrvarga biasedopioidligands AT susrutamajumdar biasedopioidligands |