Molecular determinants of biased agonism at the dopamine D₂ receptor.
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.
Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University, Schuhstraße 19, 91052 Erlangen, Germany.
Dietmar
D
Weichert
Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University, Schuhstraße 19, 91052 Erlangen, Germany.
Ashutosh
A
Banerjee
Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University, Schuhstraße 19, 91052 Erlangen, Germany.
Christine
C
Hiller
Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University, Schuhstraße 19, 91052 Erlangen, Germany.
Ralf C
RC
Kling
Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University, Schuhstraße 19, 91052 Erlangen, Germany.
Harald
H
Hübner
Department of Chemistry and Pharmacy, Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University, Schuhstraße 19, 91052 Erlangen, Germany.
Peter
P
Gmeiner
D019390:Arrestins / Q000378:metabolism; D004298:Dopamine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071557:beta-Arrestins
D019390:Arrestins; D008024:Ligands; D017448:Receptors, Dopamine D2; D000071557:beta-Arrestins; D019204:GTP-Binding Proteins; D004298:Dopamine