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-Structure paper
タイトル | Structure-based discovery of nonopioid analgesics acting through the α-adrenergic receptor. |
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ジャーナル・号・ページ | Science, Vol. 377, Issue 6614, Page eabn7065, Year 2022 |
掲載日 | 2022年9月30日 |
著者 | Elissa A Fink / Jun Xu / Harald Hübner / Joao M Braz / Philipp Seemann / Charlotte Avet / Veronica Craik / Dorothee Weikert / Maximilian F Schmidt / Chase M Webb / Nataliya A Tolmachova / Yurii S Moroz / Xi-Ping Huang / Chakrapani Kalyanaraman / Stefan Gahbauer / Geng Chen / Zheng Liu / Matthew P Jacobson / John J Irwin / Michel Bouvier / Yang Du / Brian K Shoichet / Allan I Basbaum / Peter Gmeiner / |
PubMed 要旨 | Because nonopioid analgesics are much sought after, we computationally docked more than 301 million virtual molecules against a validated pain target, the α-adrenergic receptor (αAR), seeking new ...Because nonopioid analgesics are much sought after, we computationally docked more than 301 million virtual molecules against a validated pain target, the α-adrenergic receptor (αAR), seeking new αAR agonists chemotypes that lack the sedation conferred by known αAR drugs, such as dexmedetomidine. We identified 17 ligands with potencies as low as 12 nanomolar, many with partial agonism and preferential G and G signaling. Experimental structures of αAR complexed with two of these agonists confirmed the docking predictions and templated further optimization. Several compounds, including the initial docking hit '9087 [mean effective concentration (EC) of 52 nanomolar] and two analogs, '7075 and PS75 (EC 4.1 and 4.8 nanomolar), exerted on-target analgesic activity in multiple in vivo pain models without sedation. These newly discovered agonists are interesting as therapeutic leads that lack the liabilities of opioids and the sedation of dexmedetomidine. |
リンク | Science / PubMed:36173843 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 3.4 - 3.47 Å |
構造データ | EMDB-32331, PDB-7w6p: EMDB-32342, PDB-7w7e: |
化合物 | ChemComp-W96: ChemComp-W58: |
由来 |
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キーワード | MEMBRANE PROTEIN / GPCR / G-protein / signaling complex / biased agonist |