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TitleStructure-based discovery of nonopioid analgesics acting through the α-adrenergic receptor.
Journal, issue, pagesScience, Vol. 377, Issue 6614, Page eabn7065, Year 2022
Publish dateSep 30, 2022
AuthorsElissa 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 AbstractBecause 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.
External linksScience / PubMed:36173843 / PubMed Central
MethodsEM (single particle)
Resolution3.4 - 3.47 Å
Structure data

32331

7w6p

EMDB-32331, PDB-7w6p:
Cryo-EM structure of the alpha2A adrenergic receptor GoA signaling complex bound to a G protein biased agonist
Method: EM (single particle) / Resolution: 3.47 Å

32342

7w7e

EMDB-32342, PDB-7w7e:
Cryo-EM structure of the alpha2A adrenergic receptor GoA signaling complex bound to a biased agonist
Method: EM (single particle) / Resolution: 3.4 Å

Chemicals

ChemComp-W96:
N-pyridin-4-ylisoquinolin-4-amine

ChemComp-W58:
5-(3-bicyclo[4.2.0]octa-1,3,5-trienyl)-1,2,3,6-tetrahydropyridine

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / GPCR / G-protein / signaling complex / biased agonist

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