Evaluation of the Intracellular Signaling Activities of κ-Opioid Receptor Agonists, Nalfurafine Analogs; Focusing on the Selectivity of G-Protein- and β-Arrestin-Mediated Pathways
Opioid receptors (ORs) are classified into three types (μ, δ, and κ), and opioid analgesics are mainly mediated by μOR activation; however, their use is sometimes restricted by unfavorable effects. The selective κOR agonist nalfurafine was initially developed as an analgesic, but its indication was...
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MDPI AG
2022-10-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/20/7065 |
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| author | Masahiro Yamaguchi Kanako Miyano Shigeto Hirayama Yusuke Karasawa Kaori Ohshima Eiko Uezono Akane Komatsu Miki Nonaka Hideaki Fujii Keisuke Yamaguchi Masako Iseki Masakazu Hayashida Yasuhito Uezono |
| author_facet | Masahiro Yamaguchi Kanako Miyano Shigeto Hirayama Yusuke Karasawa Kaori Ohshima Eiko Uezono Akane Komatsu Miki Nonaka Hideaki Fujii Keisuke Yamaguchi Masako Iseki Masakazu Hayashida Yasuhito Uezono |
| author_sort | Masahiro Yamaguchi |
| collection | DOAJ |
| description | Opioid receptors (ORs) are classified into three types (μ, δ, and κ), and opioid analgesics are mainly mediated by μOR activation; however, their use is sometimes restricted by unfavorable effects. The selective κOR agonist nalfurafine was initially developed as an analgesic, but its indication was changed because of the narrow safety margin. The activation of ORs mainly induces two intracellular signaling pathways: a G-protein-mediated pathway and a β-arrestin-mediated pathway. Recently, the expectations for κOR analgesics that selectively activate these pathways have increased; however, the structural properties required for the selectivity of nalfurafine are still unknown. Therefore, we evaluated the partial structures of nalfurafine that are necessary for the selectivity of these two pathways. We assayed the properties of nalfurafine and six nalfurafine analogs (SYKs) using cells stably expressing κORs. The SYKs activated κORs in a concentration-dependent manner with higher EC<sub>50</sub> values than nalfurafine. Upon bias factor assessment, only SYK-309 (possessing the 3<i>S</i>-hydroxy group) showed higher selectivity of G-protein-mediated signaling activities than nalfurafine, suggesting the direction of the 3<i>S</i>-hydroxy group may affect the β-arrestin-mediated pathway. In conclusion, nalfurafine analogs having a 3<i>S</i>-hydroxy group, such as SYK-309, could be considered G-protein-biased κOR agonists. |
| first_indexed | 2024-03-09T19:41:37Z |
| format | Article |
| id | doaj.art-a7b83951f1a546df8ff51977d03aab6c |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T19:41:37Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-a7b83951f1a546df8ff51977d03aab6c2023-11-24T01:36:46ZengMDPI AGMolecules1420-30492022-10-012720706510.3390/molecules27207065Evaluation of the Intracellular Signaling Activities of κ-Opioid Receptor Agonists, Nalfurafine Analogs; Focusing on the Selectivity of G-Protein- and β-Arrestin-Mediated PathwaysMasahiro Yamaguchi0Kanako Miyano1Shigeto Hirayama2Yusuke Karasawa3Kaori Ohshima4Eiko Uezono5Akane Komatsu6Miki Nonaka7Hideaki Fujii8Keisuke Yamaguchi9Masako Iseki10Masakazu Hayashida11Yasuhito Uezono12Department of Pain Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, JapanDepartment of Pain Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, JapanLaboratory of Medicinal Chemistry and Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, JapanDepartment of Pain Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, JapanDepartment of Pain Control Research, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, JapanDepartment of Pain Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, JapanDepartment of Anesthesiology and Pain Medicine, Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, JapanDepartment of Pain Control Research, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, JapanLaboratory of Medicinal Chemistry and Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, JapanDepartment of Pain Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, JapanDepartment of Pain Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, JapanDepartment of Pain Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, JapanDepartment of Pain Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, JapanOpioid receptors (ORs) are classified into three types (μ, δ, and κ), and opioid analgesics are mainly mediated by μOR activation; however, their use is sometimes restricted by unfavorable effects. The selective κOR agonist nalfurafine was initially developed as an analgesic, but its indication was changed because of the narrow safety margin. The activation of ORs mainly induces two intracellular signaling pathways: a G-protein-mediated pathway and a β-arrestin-mediated pathway. Recently, the expectations for κOR analgesics that selectively activate these pathways have increased; however, the structural properties required for the selectivity of nalfurafine are still unknown. Therefore, we evaluated the partial structures of nalfurafine that are necessary for the selectivity of these two pathways. We assayed the properties of nalfurafine and six nalfurafine analogs (SYKs) using cells stably expressing κORs. The SYKs activated κORs in a concentration-dependent manner with higher EC<sub>50</sub> values than nalfurafine. Upon bias factor assessment, only SYK-309 (possessing the 3<i>S</i>-hydroxy group) showed higher selectivity of G-protein-mediated signaling activities than nalfurafine, suggesting the direction of the 3<i>S</i>-hydroxy group may affect the β-arrestin-mediated pathway. In conclusion, nalfurafine analogs having a 3<i>S</i>-hydroxy group, such as SYK-309, could be considered G-protein-biased κOR agonists.https://www.mdpi.com/1420-3049/27/20/7065analgesicκ-opioid receptorG-protein-biased agonistsnalfurafinebias factor |
| spellingShingle | Masahiro Yamaguchi Kanako Miyano Shigeto Hirayama Yusuke Karasawa Kaori Ohshima Eiko Uezono Akane Komatsu Miki Nonaka Hideaki Fujii Keisuke Yamaguchi Masako Iseki Masakazu Hayashida Yasuhito Uezono Evaluation of the Intracellular Signaling Activities of κ-Opioid Receptor Agonists, Nalfurafine Analogs; Focusing on the Selectivity of G-Protein- and β-Arrestin-Mediated Pathways Molecules analgesic κ-opioid receptor G-protein-biased agonists nalfurafine bias factor |
| title | Evaluation of the Intracellular Signaling Activities of κ-Opioid Receptor Agonists, Nalfurafine Analogs; Focusing on the Selectivity of G-Protein- and β-Arrestin-Mediated Pathways |
| title_full | Evaluation of the Intracellular Signaling Activities of κ-Opioid Receptor Agonists, Nalfurafine Analogs; Focusing on the Selectivity of G-Protein- and β-Arrestin-Mediated Pathways |
| title_fullStr | Evaluation of the Intracellular Signaling Activities of κ-Opioid Receptor Agonists, Nalfurafine Analogs; Focusing on the Selectivity of G-Protein- and β-Arrestin-Mediated Pathways |
| title_full_unstemmed | Evaluation of the Intracellular Signaling Activities of κ-Opioid Receptor Agonists, Nalfurafine Analogs; Focusing on the Selectivity of G-Protein- and β-Arrestin-Mediated Pathways |
| title_short | Evaluation of the Intracellular Signaling Activities of κ-Opioid Receptor Agonists, Nalfurafine Analogs; Focusing on the Selectivity of G-Protein- and β-Arrestin-Mediated Pathways |
| title_sort | evaluation of the intracellular signaling activities of κ opioid receptor agonists nalfurafine analogs focusing on the selectivity of g protein and β arrestin mediated pathways |
| topic | analgesic κ-opioid receptor G-protein-biased agonists nalfurafine bias factor |
| url | https://www.mdpi.com/1420-3049/27/20/7065 |
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