Discovery of a Highly Selective and Potent κ Opioid Receptor Agonist from N-Cyclopropylmethyl-7α-phenyl-6,14-endoethanotetrahydronorthebaines with Reduced Central Nervous System (CNS) Side Effects Navigated by the Message–Address Concept
| Autor: | Yuanyuan Qian, Yilin Zheng, Lan Zheng, Xicheng Yang, Wei Li, Xue-Jun Xu, Mumei Zhang, Qian He, Huoming Huang, Xiao Liu, Ru-Feng Ye, Zhuibai Qiu, Congmin Yuan, Cheng Lin, Hao Chen, Rongrong Ye, Shuang Jiang, Huijiao Sun, Linqian Yu, Wei-Wei Wu, Yujun Wang, Linghui Kong, Liming Shao, Wei Fu, Dengqi Xue, Yan Ma, Qiong Xie, Hai-hao Wu, Jing-Gen Liu, Li Xiao, Shengyang Fang |
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| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
medicine.drug_class Analgesic Antagonist Pharmacology 01 natural sciences In vitro 0104 chemical sciences 010404 medicinal & biomolecular chemistry 03 medical and health sciences chemistry.chemical_compound chemistry Opioid In vivo Opioid receptor Drug Discovery medicine Molecular Medicine Benzamide Receptor 030304 developmental biology medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 62:11054-11070 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.9b00857 |
| Popis: | Effective and safe analgesics represent an unmet medical need for the treatment of acute and chronic pain. A series of N-cyclopropylmethyl-7α-phenyl-6,14-endoethanotetrahydronorthebaines were designed, synthesized, and assayed, leading to the discovery of a benzylamine derivative (compound 4, SLL-039) as a highly selective and potent κ opioid agonist (κ, Ki = 0.47 nM, κ/μ = 682, κ/δ = 283), which was confirmed by functional assays in vitro and antinociceptive assays in vivo. The in vivo effect could be blocked by pretreatment with the selective κ antagonist nor-BNI. Moreover, this compound did not induce sedation, a common dose limiting effect of κ opioid receptor agonists, at its analgesic dose compared to U50,488H. The dissociation of sedation/antinociception found in SLL-039 was assumed to be correlated with the occupation of its benzamide motif in a unique subsite involving V1182.63, W124EL1, and E209EL2. |
| Databáze: | OpenAIRE |
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