title: Structure-guided development of heterodimer-selective GPCR ligands.
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.
authors.affiliation: Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstraße 19, Erlangen 91052, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Hübner
authors.affiliation: Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstraße 19, Erlangen 91052, Germany.
authors.forename: Tamara
authors.initials: T
authors.lastname: Schellhorn
authors.affiliation: Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstraße 19, Erlangen 91052, Germany.
authors.forename: Marie
authors.initials: M
authors.lastname: Gienger
authors.affiliation: Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstraße 19, Erlangen 91052, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Schaab
authors.affiliation: Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstraße 19, Erlangen 91052, Germany.|Department of Chemistry and Pharmacy, Computer-Chemie-Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, Nägelsbachstraße 25, Erlangen 91052, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Kaindl
authors.affiliation: Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstraße 19, Erlangen 91052, Germany.
authors.forename: Laurin
authors.initials: L
authors.lastname: Leeb
authors.affiliation: Department of Chemistry and Pharmacy, Computer-Chemie-Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, Nägelsbachstraße 25, Erlangen 91052, Germany.|Centre for Molecular Design, University of Portsmouth, King Henry Building, Portsmouth PO1 2DY, UK.
authors.forename: Timothy
authors.initials: T
authors.lastname: Clark
authors.affiliation: Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstraße 19, Erlangen 91052, Germany.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Möller
authors.affiliation: Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstraße 19, Erlangen 91052, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Gmeiner
mesh_terms: D001667:Binding, Competitive; D000242:Cyclic AMP / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D055503:Protein Multimerization; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D000242:Cyclic AMP