Structure-guided development of heterodimer-selective GPCR ligands

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 (D...

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Main Authors:	Hübner, Harald, Schellhorn, Tamara, Gienger, Marie, Schaab, Carolin, Kaindl, Jonas, Leeb, Laurin, Clark, Timothy, Möller, Dorothee, Gmeiner, Peter
Format:	Online
Language:	English
Published:	Nature Publishing Group 2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4963535/

id	pubmed-4963535
recordtype	oai_dc
spelling	pubmed-49635352016-09-06 Structure-guided development of heterodimer-selective GPCR ligands Hübner, Harald Schellhorn, Tamara Gienger, Marie Schaab, Carolin Kaindl, Jonas Leeb, Laurin Clark, Timothy Möller, Dorothee Gmeiner, Peter Article 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. Nature Publishing Group 2016-07-26 /pmc/articles/PMC4963535/ /pubmed/27457610 http://dx.doi.org/10.1038/ncomms12298 Text en Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Hübner, Harald Schellhorn, Tamara Gienger, Marie Schaab, Carolin Kaindl, Jonas Leeb, Laurin Clark, Timothy Möller, Dorothee Gmeiner, Peter
spellingShingle	Hübner, Harald Schellhorn, Tamara Gienger, Marie Schaab, Carolin Kaindl, Jonas Leeb, Laurin Clark, Timothy Möller, Dorothee Gmeiner, Peter Structure-guided development of heterodimer-selective GPCR ligands
author_facet	Hübner, Harald Schellhorn, Tamara Gienger, Marie Schaab, Carolin Kaindl, Jonas Leeb, Laurin Clark, Timothy Möller, Dorothee Gmeiner, Peter
author_sort	Hübner, Harald
title	Structure-guided development of heterodimer-selective GPCR ligands
title_short	Structure-guided development of heterodimer-selective GPCR ligands
title_full	Structure-guided development of heterodimer-selective GPCR ligands
title_fullStr	Structure-guided development of heterodimer-selective GPCR ligands
title_full_unstemmed	Structure-guided development of heterodimer-selective GPCR ligands
title_sort	structure-guided development of heterodimer-selective gpcr ligands
description	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.
publisher	Nature Publishing Group
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4963535/
_version_	1613616304683483136

Structure-guided development of heterodimer-selective GPCR ligands

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