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 (D2 R/NTS1 R) heterodimers. The compounds of types 1-3 consist of three different D2 R pharmacophores bound to an affinity-generating lipophilic appendage, a polyethylene glycol-based linker and the NTS1 R 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 D2 Rs. A functional switch is observed for the bivalent ligands 3b,c inhibiting cAMP formation in cells singly expressing D2 Rs but stimulating cAMP accumulation in D2 R/NTS1 R-coexpressing cells. Moreover, the newly synthesized bivalent ligands show a strong, predominantly NTS1 R-mediated β-arrestin-2 recruitment at the D2 R/NTS1 R-coexpressing cells.