Molecular Determinants of Biased Agonism at the Dopamine D2 Receptor

被引:38
作者
Weichert, Dietmar [1 ]
Banerjee, Ashutosh [1 ]
Hiller, Christine [1 ]
Kling, Ralf C. [1 ]
Huebner, Harald [1 ]
Gmeiner, Peter [1 ]
机构
[1] Univ Erlangen Nurnberg, Emil Fischer Ctr, Med Chem, Dept Chem & Pharm, D-91052 Erlangen, Germany
关键词
NONAROMATIC CATECHOL BIOISOSTERES; PROTEIN-REGULATED INDUCER; FUNCTIONAL SELECTIVITY; NEURITE OUTGROWTH; DISCOVERY; MULTIPLE; D3; DISTINCT; LIGANDS; ALPHA(2A)-ADRENOCEPTOR;
D O I
10.1021/jm501889t
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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 D-2 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 D-2 receptors. Whereas the (S)-enantiomer behaved as a full agonist, the biased ligand (R)-4 induced poor G protein coupling but substantial beta-arrestin recruitment.
引用
收藏
页码:2703 / 2717
页数:15
相关论文
共 50 条
  • [21] Structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone
    Wang, Sheng
    Che, Tao
    Levit, Anat
    Shoichet, Brian K.
    Wacker, Daniel
    Roth, Bryan L.
    NATURE, 2018, 555 (7695) : 269 - +
  • [22] Effects of β-Arrestin-Biased Dopamine D2 Receptor Ligands on Schizophrenia-Like Behavior in Hypoglutamatergic Mice
    Park, Su M.
    Chen, Meng
    Schmerberg, Claire M.
    Dulman, Russell S.
    Rodriguiz, Ramona M.
    Caron, Marc G.
    Jin, Jian
    Wetsel, William C.
    NEUROPSYCHOPHARMACOLOGY, 2016, 41 (03) : 704 - 715
  • [23] Structure-Activity Relationships of Privileged Structures Lead to the Discovery of Novel Biased Ligands at the Dopamine D2 Receptor
    Szabo, Monika
    Herenbrink, Carmen Klein
    Christopoulos, Arthur
    Lane, J. Robert
    Capuano, Ben
    JOURNAL OF MEDICINAL CHEMISTRY, 2014, 57 (11) : 4924 - 4939
  • [24] Efficacy of Dopamine D2 Receptor β-Arrestin-Biased Ligands on Schizophrenia-Like Behaviors in Mutant Mice
    Wetsel, William C.
    Schmerberg, Claire M.
    Chen, Meng
    Rodriguiz, Ramona M.
    Park, Su Mi
    Chen, Xin
    Caron, Marc G.
    Jin, Jian
    NEUROPSYCHOPHARMACOLOGY, 2015, 40 : S551 - S551
  • [25] A Unique Dual Cortico-Striatal Action of a Beta-Arrestin Biased Dopamine D2 Receptor Ligand
    Urs, Nikhil
    Gee, Steven
    McCorvy, John
    Pack, Thomas
    Evron, Tama
    Roth, Bryan
    O'Donnell, Patricio
    Caron, Marc
    NEUROPSYCHOPHARMACOLOGY, 2015, 40 : S210 - S211
  • [26] Aromatic linker variations in novel dopamine D2 and D3 receptor ligands
    Di Biase, Cristian
    Leitzbach, Luisa
    Frank, Annika
    Zivkovic, Aleksandra
    Stark, Holger
    ARCHIV DER PHARMAZIE, 2024, 357 (08)
  • [27] Molecular Determinants of Selectivity and Efficacy at the Dopamine D3 Receptor
    Newman, Amy Hauck
    Beuming, Thijs
    Banala, Ashwini K.
    Donthamsett, Prashant
    Pongetti, Katherine
    LaBounty, Alex
    Levy, Benjamin
    Cao, Jianjing
    Michino, Mayako
    Luedtke, Robert R.
    Javitch, Jonathan A.
    Shi, Lei
    JOURNAL OF MEDICINAL CHEMISTRY, 2012, 55 (15) : 6689 - 6699
  • [28] Discovery of a true bivalent dopamine D2 receptor agonist
    Qian, Mingcheng
    Ricarte, Adrian
    Wouters, Elise
    Dalton, James A. R.
    Risseeuw, Martijn D. P.
    Giraldo, Jesus
    Van Calenbergh, Serge
    EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2021, 212
  • [29] Dopamine D2, D3, and D4 Selective Phenylpiperazines as Molecular Probes To Explore the Origins of Subtype Specific Receptor Binding
    Ehrlich, Katharina
    Gotz, Angela
    Bollinger, Stefan
    Tschammer, Nuska
    Bettinetti, Laura
    Harterich, Steffen
    Hubner, Harald
    Lanig, Harald
    Gmeiner, Peter
    JOURNAL OF MEDICINAL CHEMISTRY, 2009, 52 (15) : 4923 - 4935
  • [30] Distinct inactive conformations of the dopamine D2 and D3 receptors correspond to different extents of inverse agonism
    Lane, J. Robert
    Abramyan, Ara M.
    Adhikari, Pramisha
    Keen, Alastair C.
    Lee, Kuo-Hao
    Sanchez, Julie
    Verma, Ravi Kumar
    Lim, Herman D.
    Yano, Hideaki
    Javitch, Jonathan A.
    Shi, Lei
    ELIFE, 2020, 9