Molecular Determinants of Biased Agonism at the Dopamine D₂Receptor

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.

Identification of the Beer Component Hordenine as Food-Derived Dopamine D2 Receptor Agonist by Virtual Screening a 3D Compound Database

“…The measurement of β-arrestin-2 recruitment stimulated by D2R activation was performed using the PathHunter® assay purchased from DiscoveRx (Birmingham, U.K.) according to the manufacturer’s protocol as described previously47. To determine the antagonist properties, different concentrations of the test compounds (10 −10 –10 −3  M) were pre-incubated for 30 min before adding 300 nM (final concentration) quinpirole to start the standard incubation period.…”

Synthesis, Biological, and Computational Evaluation of Substituted 1‐(2‐Methoxyphenyl)‐4‐(1‐phenethylpiperidin‐4‐yl)piperazines and 1‐(2‐Methoxyphenyl)‐4‐[(1‐phenethylpiperidin‐4‐yl)methyl]piperazines as Dopaminergic Ligands

“…Affinity in itself toward D 2 DAR ( K i , Table ) does not tell us much about biological activity of the compounds; arylpiperazines can be acting as D 2 dopaminergic agonist, partial agonist or antagonist and can exert their effect through different signaling pathways . Prediction of biological activity for dopaminergic arylpiperazines in silico can be available soon because of the recent progress in the field . This similarly holds through for the prediction of ligand selectivity where, in this case, D 2 DAR versus D 3 DAR selectivity is of particular interest .…”

“…General procedure for the synthesis of compounds (11)(12)(13)(14)(15)(16)(17)(18) Solution of acid 7-10 (0.0149 mol), compound 5 or 6 (0.0149 mol), DCC (0.028 mol) in CH 3 CN (10 mL) was stirred at 0°C for 0.5 h and after that, stirring was continued at r.t for 24 h. Reaction mixture was filtered, organic layer was washed with NaHCO 3 , dried over anhydrous Na 2 SO 4 , and evaporated in vacuo. General procedure for reduction of the compounds 19-26…”

Synthesis and evaluation of radioiodinated 1-{2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl}piperidin-4-amine derivatives for platelet-derived growth factor receptor β (PDGFRβ) imaging

“…Intermediate and reference compounds, IQP, ATE, and SIB, were synthesized according to the reported studies, with a slight modification. [32][33][34][35][36][37] Detailed procedures were shown in the Supporting Information.…”