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Molecular determinants of biased agonism at the dopamine D₂ receptor. | LitMetric

Molecular determinants of biased agonism at the dopamine D₂ receptor.

J Med Chem

Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University, Schuhstraße 19, 91052 Erlangen, Germany.

Published: March 2015

AI Article Synopsis

  • The study focuses on creating biased ligands for the dopamine D2 receptor, which are crucial for drug development in medicinal chemistry.* -
  • Researchers synthesized various agonists with different structural properties, discovering that those derived from atypical pharmacophores promote biased signaling, while classic ones tend to produce balanced responses.* -
  • The study highlights how the stereochemistry of a specific class of agonists significantly affects their functional selectivity, with the (S)-enantiomer acting as a strong agonist and the (R)-4 variant showing limited G protein interaction but increased recruitment of β-arrestin.*

Article 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.

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm501889tDOI Listing

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