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.

journal_name

Nat Commun

journal_title

Nature communications

authors

Hübner H,Schellhorn T,Gienger M,Schaab C,Kaindl J,Leeb L,Clark T,Möller D,Gmeiner P

doi

10.1038/ncomms12298

subject

Has Abstract

pub_date

2016-07-26 00:00:00

pages

12298

issn

2041-1723

pii

ncomms12298

journal_volume

7

pub_type

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