Summary for 9I52
| Entry DOI | 10.2210/pdb9i52/pdb |
| EMDB information | 52624 |
| Descriptor | Beta-2 adrenergic receptor,D(1A) dopamine receptor, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total) |
| Functional Keywords | d1r, gs, agonist, parkinson, neuroscience, d1r gs, hormone |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 151673.98 |
| Authors | Clairfeuille, T.,Rodriguez Sarmiento, R.M. (deposition date: 2025-01-27, release date: 2025-07-16, Last modification date: 2025-07-23) |
| Primary citation | Rodriguez Sarmiento, R.M.,Berchtold, S.,Manevski, N.,Lindemann, L.,Dey, F.,Clairfeuille, T.,Amendola, D.,Vautrelle, N.,Duveau, V.,O Connor, E.C. Orally Bioavailable Dopamine D1/D5 Receptor-Biased Agonists to Study the Role of beta-Arrestin in Treatment-Related Dyskinesia in Parkinson's Disease. J.Med.Chem., 68:13532-13561, 2025 Cited by PubMed Abstract: Dopamine replacement therapies for Parkinson's disease often produce dyskinesias with long-term use. Published studies suggest that introducing β-arrestin signaling might be protective for dyskinesia. We advanced known noncatecholamine D1/D5 receptor G protein-biased agonists and found that removal of oxygen in the linker from published compounds limited β-arrestin recruitment, whereas introduction of nitrogen on the central -phenyl linker favored β-arrestin recruitment and provided orally bioavailable compounds. Cryogenic electron microscopy suggested key receptor-ligand interactions influencing the different bias behaviors. We discovered compound , a D1/D5 receptor agonist with β-arrestin recruitment and properties for use . We compared with tavapadon, which shows weak efficacy for β-arrestin signaling, in a rat model of Parkinson's disease with L-DOPA-induced dyskinesias. At particular doses, compound produced efficacy comparable to L-DOPA, but with fewer concomitant dyskinesias. This first study suggests that β-arrestin may have a positive influence on reducing dyskinesias following acute administration. PubMed: 40552668DOI: 10.1021/acs.jmedchem.5c00294 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.8 Å) |
Structure validation
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