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Structure-guided development of heterodimer-selective GPCR ligands

Author

Listed:
  • Harald Hübner

    (Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg)

  • Tamara Schellhorn

    (Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg)

  • Marie Gienger

    (Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg)

  • Carolin Schaab

    (Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg)

  • Jonas Kaindl

    (Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg
    Computer-Chemie-Center, Friedrich-Alexander-Universität Erlangen-Nürnberg)

  • Laurin Leeb

    (Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg)

  • Timothy Clark

    (Computer-Chemie-Center, Friedrich-Alexander-Universität Erlangen-Nürnberg
    Centre for Molecular Design, University of Portsmouth)

  • Dorothee Möller

    (Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg)

  • Peter Gmeiner

    (Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg)

Abstract

Crystal structures of G protein-coupled receptor (GPCR) ligand complexes allow a rational design of novel molecular probes and drugs. Here we report the structure-guided design, chemical synthesis and biological investigations of bivalent ligands for dopamine D2 receptor/neurotensin NTS1 receptor (D2R/NTS1R) heterodimers. The compounds of types 1–3 consist of three different D2R pharmacophores bound to an affinity-generating lipophilic appendage, a polyethylene glycol-based linker and the NTS1R agonist NT(8-13). The bivalent ligands show binding affinity in the picomolar range for cells coexpressing both GPCRs and unprecedented selectivity (up to three orders of magnitude), compared with cells that only express D2Rs. A functional switch is observed for the bivalent ligands 3b,c inhibiting cAMP formation in cells singly expressing D2Rs but stimulating cAMP accumulation in D2R/NTS1R-coexpressing cells. Moreover, the newly synthesized bivalent ligands show a strong, predominantly NTS1R-mediated β-arrestin-2 recruitment at the D2R/NTS1R-coexpressing cells.

Suggested Citation

  • Harald Hübner & Tamara Schellhorn & Marie Gienger & Carolin Schaab & Jonas Kaindl & Laurin Leeb & Timothy Clark & Dorothee Möller & Peter Gmeiner, 2016. "Structure-guided development of heterodimer-selective GPCR ligands," Nature Communications, Nature, vol. 7(1), pages 1-12, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12298
    DOI: 10.1038/ncomms12298
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    Cited by:

    1. Xinyu Xu & Jeremy Shonberg & Jonas Kaindl & Mary J. Clark & Anne Stößel & Luis Maul & Daniel Mayer & Harald Hübner & Kunio Hirata & A. J. Venkatakrishnan & Ron O. Dror & Brian K. Kobilka & Roger K. Su, 2023. "Constrained catecholamines gain β2AR selectivity through allosteric effects on pocket dynamics," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Jun Xu & Qinggong Wang & Harald Hübner & Yunfei Hu & Xiaogang Niu & Haoqing Wang & Shoji Maeda & Asuka Inoue & Yuyong Tao & Peter Gmeiner & Yang Du & Changwen Jin & Brian K. Kobilka, 2023. "Structural and dynamic insights into supra-physiological activation and allosteric modulation of a muscarinic acetylcholine receptor," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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