IUPHAR themed review: Opioid efficacy, bias, and selectivity
Drugs acting at the opioid receptor family are clinically used to treat chronic and acute pain, though they represent the second line of treatment behind GABA analogs, antidepressants and SSRI’s. Within the opioid family mu and kappa opioid receptor are commonly targeted. However, activation of the...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-11-01
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| Series: | Pharmacological Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661823003171 |
| _version_ | 1797582973809197056 |
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| author | Nokomis Ramos-Gonzalez Barnali Paul Susruta Majumdar |
| author_facet | Nokomis Ramos-Gonzalez Barnali Paul Susruta Majumdar |
| author_sort | Nokomis Ramos-Gonzalez |
| collection | DOAJ |
| description | Drugs acting at the opioid receptor family are clinically used to treat chronic and acute pain, though they represent the second line of treatment behind GABA analogs, antidepressants and SSRI’s. Within the opioid family mu and kappa opioid receptor are commonly targeted. However, activation of the mu opioid receptor has side effects of constipation, tolerance, dependence, euphoria, and respiratory depression; activation of the kappa opioid receptor leads to dysphoria and sedation. The side effects of mu opioid receptor activation have led to mu receptor drugs being widely abused with great overdose risk. For these reasons, newer safer opioid analgesics are in high demand. For many years a focus within the opioid field was finding drugs that activated the G protein pathway at mu opioid receptor, without activating the β-arrestin pathway, known as biased agonism. Recent advances have shown that this may not be the way forward to develop safer analgesics at mu opioid receptor, though there is still some promise at the kappa opioid receptor. Here we discuss recent novel approaches to develop safer opioid drugs including efficacy vs bias and fine-tuning receptor activation by targeting sub-pockets in the orthosteric site, we explore recent works on the structural basis of bias, and we put forward the suggestion that Gα subtype selectivity may be an exciting new area of interest. |
| first_indexed | 2024-03-10T23:30:13Z |
| format | Article |
| id | doaj.art-efc1fe6a0e4f48d0ab3343f086f280de |
| institution | Directory Open Access Journal |
| issn | 1096-1186 |
| language | English |
| last_indexed | 2024-03-10T23:30:13Z |
| publishDate | 2023-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj.art-efc1fe6a0e4f48d0ab3343f086f280de2023-11-19T04:34:17ZengElsevierPharmacological Research1096-11862023-11-01197106961IUPHAR themed review: Opioid efficacy, bias, and selectivityNokomis Ramos-Gonzalez0Barnali Paul1Susruta Majumdar2Department of Anesthesiology and Washington University Pain Center, Washington University School of Medicine, Saint Louis, MO, USA; Center for Clinical Pharmacology, University of Health Sciences & Pharmacy at St. Louis and Washington University School of Medicine, St. Louis, MO, USADepartment of Anesthesiology and Washington University Pain Center, Washington University School of Medicine, Saint Louis, MO, USA; Center for Clinical Pharmacology, University of Health Sciences & Pharmacy at St. Louis and Washington University School of Medicine, St. Louis, MO, USADepartment of Anesthesiology and Washington University Pain Center, Washington University School of Medicine, Saint Louis, MO, USA; Center for Clinical Pharmacology, University of Health Sciences & Pharmacy at St. Louis and Washington University School of Medicine, St. Louis, MO, USA; Corresponding author at: Department of Anesthesiology and Washington University Pain Center, Washington University School of Medicine, Saint Louis, MO, USA.Drugs acting at the opioid receptor family are clinically used to treat chronic and acute pain, though they represent the second line of treatment behind GABA analogs, antidepressants and SSRI’s. Within the opioid family mu and kappa opioid receptor are commonly targeted. However, activation of the mu opioid receptor has side effects of constipation, tolerance, dependence, euphoria, and respiratory depression; activation of the kappa opioid receptor leads to dysphoria and sedation. The side effects of mu opioid receptor activation have led to mu receptor drugs being widely abused with great overdose risk. For these reasons, newer safer opioid analgesics are in high demand. For many years a focus within the opioid field was finding drugs that activated the G protein pathway at mu opioid receptor, without activating the β-arrestin pathway, known as biased agonism. Recent advances have shown that this may not be the way forward to develop safer analgesics at mu opioid receptor, though there is still some promise at the kappa opioid receptor. Here we discuss recent novel approaches to develop safer opioid drugs including efficacy vs bias and fine-tuning receptor activation by targeting sub-pockets in the orthosteric site, we explore recent works on the structural basis of bias, and we put forward the suggestion that Gα subtype selectivity may be an exciting new area of interest.http://www.sciencedirect.com/science/article/pii/S1043661823003171OpioidMuKappaGα-subtype biasSelectivityEfficacy |
| spellingShingle | Nokomis Ramos-Gonzalez Barnali Paul Susruta Majumdar IUPHAR themed review: Opioid efficacy, bias, and selectivity Pharmacological Research Opioid Mu Kappa Gα-subtype bias Selectivity Efficacy |
| title | IUPHAR themed review: Opioid efficacy, bias, and selectivity |
| title_full | IUPHAR themed review: Opioid efficacy, bias, and selectivity |
| title_fullStr | IUPHAR themed review: Opioid efficacy, bias, and selectivity |
| title_full_unstemmed | IUPHAR themed review: Opioid efficacy, bias, and selectivity |
| title_short | IUPHAR themed review: Opioid efficacy, bias, and selectivity |
| title_sort | iuphar themed review opioid efficacy bias and selectivity |
| topic | Opioid Mu Kappa Gα-subtype bias Selectivity Efficacy |
| url | http://www.sciencedirect.com/science/article/pii/S1043661823003171 |
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