Molecular determinants of biased agonism at the dopamine D₂ receptor.
Basic Information
ID: ALA3576771
Journal: J Med Chem
Title: Molecular determinants of biased agonism at the dopamine D₂ receptor.
Authors: Weichert D, Banerjee A, Hiller C, Kling RC, Hübner H, Gmeiner P.
Abstract: The development of biased (functionally selective) ligands provides a formidable challenge in medicinal chemistry. In an effort to learn to design functionally selective molecular tools for the highly therapeutically relevant dopamine D2 receptor, we synthesized a collection of agonists based on structurally distinct head groups derived from canonical or atypical dopaminergic pharmacophores. The test compounds feature a long lipophilic appendage that was shown to mediate biased signaling. By employing functional assays and molecular dynamics simulations, we could show that atypical dopamine surrogates of type 1 and 2 promote biased signaling, while ligands built from classical dopaminergic head groups (type 3 and 4) typically elicit more balanced signaling profiles. Besides this, we found a strong influence of the stereochemistry of type 4 aminotetraline-derived agonists on functional selectivity at D2 receptors. Whereas the (S)-enantiomer behaved as a full agonist, the biased ligand (R)-4 induced poor G protein coupling but substantial β-arrestin recruitment.
CiteXplore: 25734236
DOI: 10.1021/jm501889t
Patent ID: ┄