Structure-guided development of heterodimer-selective GPCR ligands

Harald Hübner, Tamara Schellhorn, Marie Gienger, Carolin Schaab, Jonas Kaindl, Laurin Leeb, Timothy Clark, Dorothee Möller () and Peter Gmeiner ()
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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
Laurin Leeb: Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg
Timothy Clark: Computer-Chemie-Center, Friedrich-Alexander-Universität Erlangen-Nürnberg
Dorothee Möller: Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg
Peter Gmeiner: Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: 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.

Date: 2016
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12298

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DOI: 10.1038/ncomms12298

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