Synthesis and biological evaluation of a peptide-remifentanil conjugate as a novel bifunctional mu/delta-opioid receptor agonist for the treatment of pain
For the treatment of pain, the design of a bifunctional mu-opioid receptor (MOR)/delta-opioid receptor (DOR) agonist is an effective strategy to seek safer opioids with higher antinociceptive efficacy and diminished adverse side effects. Herein, we describe the design, synthesis, and evaluation of a...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-08-01
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| Series: | Arabian Journal of Chemistry |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S187853522300480X |
| _version_ | 1827925803762974720 |
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| author | Lu Wang Jing Li Fengxia Ren Hongxin Jia Zixing Yu Jingchao Cheng Tao Zhang Weiguo Shi Xuesong Feng |
| author_facet | Lu Wang Jing Li Fengxia Ren Hongxin Jia Zixing Yu Jingchao Cheng Tao Zhang Weiguo Shi Xuesong Feng |
| author_sort | Lu Wang |
| collection | DOAJ |
| description | For the treatment of pain, the design of a bifunctional mu-opioid receptor (MOR)/delta-opioid receptor (DOR) agonist is an effective strategy to seek safer opioids with higher antinociceptive efficacy and diminished adverse side effects. Herein, we describe the design, synthesis, and evaluation of a novel bivalent ligand (SW-WL-2) with a methyl 1-(3-methoxy-3-oxopropyl)-4-(phenylamino) piperidine- 4-carboxylate moiety (remifentanil derivative) covalently linked to a dermorphin-like structure (H-Dmt-N-Me-D-Ala-Aba-Gly-NH2, BVD03) at the C-terminus. Our results showed that SW-WL-2 behaved as a potent dual agonist of MOR and DOR with significant and prolonged antinociceptive effects in acute pain models in vivo. Furthermore, SW-WL-2 exhibited reduced or no opioid-like side effects such as physical dependence or respiratory depression, in contrast to an equipotent analgesic dose of morphine or BVD03. Thus, SW-WL-2 should be used as a new lead compound for the discovery of safer opioid drugs for the treatment of pain. |
| first_indexed | 2024-03-13T05:29:25Z |
| format | Article |
| id | doaj.art-63137ff92a5342cdb7c6e1a5468c7d35 |
| institution | Directory Open Access Journal |
| issn | 1878-5352 |
| language | English |
| last_indexed | 2024-03-13T05:29:25Z |
| publishDate | 2023-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Arabian Journal of Chemistry |
| spelling | doaj.art-63137ff92a5342cdb7c6e1a5468c7d352023-06-15T04:55:14ZengElsevierArabian Journal of Chemistry1878-53522023-08-01168105018Synthesis and biological evaluation of a peptide-remifentanil conjugate as a novel bifunctional mu/delta-opioid receptor agonist for the treatment of painLu Wang0Jing Li1Fengxia Ren2Hongxin Jia3Zixing Yu4Jingchao Cheng5Tao Zhang6Weiguo Shi7Xuesong Feng8School of Pharmacy, China Medical University, 77 Pu-He Road, Shenyang 110122, China; State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, ChinaState Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, ChinaState Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, ChinaState Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, ChinaState Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, ChinaState Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, ChinaState Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, China; Corresponding authors.State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, China; Corresponding authors.School of Pharmacy, China Medical University, 77 Pu-He Road, Shenyang 110122, China; Corresponding authors.For the treatment of pain, the design of a bifunctional mu-opioid receptor (MOR)/delta-opioid receptor (DOR) agonist is an effective strategy to seek safer opioids with higher antinociceptive efficacy and diminished adverse side effects. Herein, we describe the design, synthesis, and evaluation of a novel bivalent ligand (SW-WL-2) with a methyl 1-(3-methoxy-3-oxopropyl)-4-(phenylamino) piperidine- 4-carboxylate moiety (remifentanil derivative) covalently linked to a dermorphin-like structure (H-Dmt-N-Me-D-Ala-Aba-Gly-NH2, BVD03) at the C-terminus. Our results showed that SW-WL-2 behaved as a potent dual agonist of MOR and DOR with significant and prolonged antinociceptive effects in acute pain models in vivo. Furthermore, SW-WL-2 exhibited reduced or no opioid-like side effects such as physical dependence or respiratory depression, in contrast to an equipotent analgesic dose of morphine or BVD03. Thus, SW-WL-2 should be used as a new lead compound for the discovery of safer opioid drugs for the treatment of pain.http://www.sciencedirect.com/science/article/pii/S187853522300480XSafer opioidsPeptide-fentanyl conjugateBifunctional mu/delta opioid receptor agonistsAntinociceptiveBivalent ligands |
| spellingShingle | Lu Wang Jing Li Fengxia Ren Hongxin Jia Zixing Yu Jingchao Cheng Tao Zhang Weiguo Shi Xuesong Feng Synthesis and biological evaluation of a peptide-remifentanil conjugate as a novel bifunctional mu/delta-opioid receptor agonist for the treatment of pain Arabian Journal of Chemistry Safer opioids Peptide-fentanyl conjugate Bifunctional mu/delta opioid receptor agonists Antinociceptive Bivalent ligands |
| title | Synthesis and biological evaluation of a peptide-remifentanil conjugate as a novel bifunctional mu/delta-opioid receptor agonist for the treatment of pain |
| title_full | Synthesis and biological evaluation of a peptide-remifentanil conjugate as a novel bifunctional mu/delta-opioid receptor agonist for the treatment of pain |
| title_fullStr | Synthesis and biological evaluation of a peptide-remifentanil conjugate as a novel bifunctional mu/delta-opioid receptor agonist for the treatment of pain |
| title_full_unstemmed | Synthesis and biological evaluation of a peptide-remifentanil conjugate as a novel bifunctional mu/delta-opioid receptor agonist for the treatment of pain |
| title_short | Synthesis and biological evaluation of a peptide-remifentanil conjugate as a novel bifunctional mu/delta-opioid receptor agonist for the treatment of pain |
| title_sort | synthesis and biological evaluation of a peptide remifentanil conjugate as a novel bifunctional mu delta opioid receptor agonist for the treatment of pain |
| topic | Safer opioids Peptide-fentanyl conjugate Bifunctional mu/delta opioid receptor agonists Antinociceptive Bivalent ligands |
| url | http://www.sciencedirect.com/science/article/pii/S187853522300480X |
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