A Review of the Therapeutic Potential of Recently Developed G Protein-Biased Kappa Agonists
Between 2000 and 2005 several studies revealed that morphine is more potent and exhibits fewer side effects in beta-arrestin 2 knockout mice. These findings spurred efforts to develop opioids that signal primarily via G protein activation and do not, or only very weakly, recruit beta-arrestin. Devel...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-04-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2019.00407/full |
| _version_ | 1811326632615477248 |
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| author | Kendall L. Mores Benjamin R. Cummins Robert J. Cassell Robert J. Cassell Richard M. van Rijn Richard M. van Rijn Richard M. van Rijn |
| author_facet | Kendall L. Mores Benjamin R. Cummins Robert J. Cassell Robert J. Cassell Richard M. van Rijn Richard M. van Rijn Richard M. van Rijn |
| author_sort | Kendall L. Mores |
| collection | DOAJ |
| description | Between 2000 and 2005 several studies revealed that morphine is more potent and exhibits fewer side effects in beta-arrestin 2 knockout mice. These findings spurred efforts to develop opioids that signal primarily via G protein activation and do not, or only very weakly, recruit beta-arrestin. Development of such molecules targeting the mu opioid receptor initially outpaced those targeting the kappa, delta and nociceptin opioid receptors, with the G protein-biased mu opioid agonist oliceridine/TRV130 having completed phase III clinical trials with improved therapeutic window to treat moderate-to-severe acute pain. Recently however, there has been a sharp increase in the development of novel G protein-biased kappa agonists. It is hypothesized that G protein-biased kappa agonists can reduce pain and itch, but exhibit fewer side effects, such as anhedonia and psychosis, that have thus far limited the clinical development of unbiased kappa opioid agonists. Here we summarize recently discovered G protein-biased kappa agonists, comparing structures, degree of signal bias and preclinical effects. We specifically reviewed nalfurafine, 22-thiocyanatosalvinorin A (RB-64), mesyl-salvinorin B, 2-(4-(furan-2-ylmethyl)-5-((4-methyl-3-(trifluoromethyl)benzyl)thio)-4H-1,2,4-triazol-3-yl)pyridine (triazole 1.1), 3-(2-((cyclopropylmethyl)(phenethyl)amino)ethyl)phenol (HS666), N-n-butyl-N-phenylethyl-N-3-hydroxyphenylethyl-amine (compound 5/BPHA), 6-guanidinonaltrindole (6′GNTI), and collybolide. These agonists encompass a variety of chemical scaffolds and range in both their potency and efficacy in terms of G protein signaling and beta-arrestin recruitment. Thus unsurprisingly, the behavioral responses reported for these agonists are not uniform. Yet, it is our conclusion that the kappa opioid field will benefit tremendously from future studies that compare several biased agonists and correlate the degree of signaling bias to a particular pharmacological response. |
| first_indexed | 2024-04-13T14:53:12Z |
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| id | doaj.art-3dde103f05cd4c3d9c9964c97367eed2 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-13T14:53:12Z |
| publishDate | 2019-04-01 |
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| spelling | doaj.art-3dde103f05cd4c3d9c9964c97367eed22022-12-22T02:42:32ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122019-04-011010.3389/fphar.2019.00407447554A Review of the Therapeutic Potential of Recently Developed G Protein-Biased Kappa AgonistsKendall L. Mores0Benjamin R. Cummins1Robert J. Cassell2Robert J. Cassell3Richard M. van Rijn4Richard M. van Rijn5Richard M. van Rijn6Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, West Lafayette, IN, United StatesDepartment of Chemistry, College of Science, West Lafayette, IN, United StatesDepartment of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, West Lafayette, IN, United StatesPurdue Institute for Drug Discovery, West Lafayette, IN, United StatesDepartment of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, West Lafayette, IN, United StatesPurdue Institute for Drug Discovery, West Lafayette, IN, United StatesPurdue Institute for Integrative Neuroscience, West Lafayette, IN, United StatesBetween 2000 and 2005 several studies revealed that morphine is more potent and exhibits fewer side effects in beta-arrestin 2 knockout mice. These findings spurred efforts to develop opioids that signal primarily via G protein activation and do not, or only very weakly, recruit beta-arrestin. Development of such molecules targeting the mu opioid receptor initially outpaced those targeting the kappa, delta and nociceptin opioid receptors, with the G protein-biased mu opioid agonist oliceridine/TRV130 having completed phase III clinical trials with improved therapeutic window to treat moderate-to-severe acute pain. Recently however, there has been a sharp increase in the development of novel G protein-biased kappa agonists. It is hypothesized that G protein-biased kappa agonists can reduce pain and itch, but exhibit fewer side effects, such as anhedonia and psychosis, that have thus far limited the clinical development of unbiased kappa opioid agonists. Here we summarize recently discovered G protein-biased kappa agonists, comparing structures, degree of signal bias and preclinical effects. We specifically reviewed nalfurafine, 22-thiocyanatosalvinorin A (RB-64), mesyl-salvinorin B, 2-(4-(furan-2-ylmethyl)-5-((4-methyl-3-(trifluoromethyl)benzyl)thio)-4H-1,2,4-triazol-3-yl)pyridine (triazole 1.1), 3-(2-((cyclopropylmethyl)(phenethyl)amino)ethyl)phenol (HS666), N-n-butyl-N-phenylethyl-N-3-hydroxyphenylethyl-amine (compound 5/BPHA), 6-guanidinonaltrindole (6′GNTI), and collybolide. These agonists encompass a variety of chemical scaffolds and range in both their potency and efficacy in terms of G protein signaling and beta-arrestin recruitment. Thus unsurprisingly, the behavioral responses reported for these agonists are not uniform. Yet, it is our conclusion that the kappa opioid field will benefit tremendously from future studies that compare several biased agonists and correlate the degree of signaling bias to a particular pharmacological response.https://www.frontiersin.org/article/10.3389/fphar.2019.00407/fullkappa opioid receptorbeta-arrestinG proteinsignaling biasnalfurafinediphenethylamine |
| spellingShingle | Kendall L. Mores Benjamin R. Cummins Robert J. Cassell Robert J. Cassell Richard M. van Rijn Richard M. van Rijn Richard M. van Rijn A Review of the Therapeutic Potential of Recently Developed G Protein-Biased Kappa Agonists Frontiers in Pharmacology kappa opioid receptor beta-arrestin G protein signaling bias nalfurafine diphenethylamine |
| title | A Review of the Therapeutic Potential of Recently Developed G Protein-Biased Kappa Agonists |
| title_full | A Review of the Therapeutic Potential of Recently Developed G Protein-Biased Kappa Agonists |
| title_fullStr | A Review of the Therapeutic Potential of Recently Developed G Protein-Biased Kappa Agonists |
| title_full_unstemmed | A Review of the Therapeutic Potential of Recently Developed G Protein-Biased Kappa Agonists |
| title_short | A Review of the Therapeutic Potential of Recently Developed G Protein-Biased Kappa Agonists |
| title_sort | review of the therapeutic potential of recently developed g protein biased kappa agonists |
| topic | kappa opioid receptor beta-arrestin G protein signaling bias nalfurafine diphenethylamine |
| url | https://www.frontiersin.org/article/10.3389/fphar.2019.00407/full |
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