Structure-guided development of heterodimer-selective GPCR ligands

Journal article
(Original article)

Publication Details

Author(s): Hübner H, Schellhorn T, Gienger M, Schaab C, Kaindl J, Leeb L, Clark T, Möller D, Gmeiner P
Journal: Nature Communications
Publisher: Nature Publishing Group: Nature Communications
Publication year: 2016
Volume: 7
Pages range: 12298
ISSN: 2041-1723
Language: English


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 D-2 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 D(2)Rs. A functional switch is observed for the bivalent ligands 3b,c inhibiting cAMP formation in cells singly expressing D(2)Rs but stimulating cAMP accumulation in D2R/NTS1R-coexpressing cells. Moreover, the newly synthesized bivalent ligands show a strong, predominantly NTS1R-mediated beta-arrestin-2 recruitment at the D2R/NTS1R-coexpressing cells.

FAU Authors / FAU Editors

Clark, Timothy apl. Prof. Dr.
Gienger, Marie
Lehrstuhl für Pharmazeutische Chemie
Gmeiner, Peter Prof. Dr.
Lehrstuhl für Pharmazeutische Chemie
Hübner, Harald Dr.
Lehrstuhl für Pharmazeutische Chemie
Kaindl, Jonas
Lehrstuhl für Pharmazeutische Chemie
Leeb, Laurin
Lehrstuhl für Pharmazeutische Chemie
Weikert, Dorothee Dr.
Lehrstuhl für Pharmazeutische Chemie
Schaab, Carolin
Lehrstuhl für Pharmazeutische Chemie
Schellhorn, Tamara
Lehrstuhl für Pharmazeutische Chemie

Additional Organisation
Emil-Fischer-Zentrum (Emil Fischer Center)

How to cite

Hübner, H., Schellhorn, T., Gienger, M., Schaab, C., Kaindl, J., Leeb, L.,... Gmeiner, P. (2016). Structure-guided development of heterodimer-selective GPCR ligands. Nature Communications, 7, 12298.

Hübner, Harald, et al. "Structure-guided development of heterodimer-selective GPCR ligands." Nature Communications 7 (2016): 12298.


Last updated on 2019-18-07 at 07:24