9I54

Dopamine 1 receptor:GaS complex bound to 24

これはPDB形式変換不可エントリーです。

9I54 の概要

• エントリーDOI: 10.2210/pdb9i54/pdb
• 関連するPDBエントリー: 9I52
• EMDBエントリー: 52624 52625
• 分子名称: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, 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)
• 機能のキーワード: d1r, gs, agonist, parkinson, neuroscience, d1r gs, hormone
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 151695.92

構造登録者

Clairfeuille, T.,Rodriguez Sarmiento, R.M. (登録日: 2025-01-27, 公開日: 2025-07-16, 最終更新日: 2025-07-23)

主引用文献

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

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: 40552668
DOI: 10.1021/acs.jmedchem.5c00294

実験手法

ELECTRON MICROSCOPY (2.72 Å)