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 D 2 receptor/neurotensin NTS 1 receptor (D 2 R/NTS 1 R) heterodimers. The compounds of types 1–3 consist of three different D 2 R pharmacophores bound to an affinity-generating lipophilic appendage, a polyethylene glycol-based linker and the NTS 1 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 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 D 2 R/NTS 1 R-coexpressing cells. Moreover, the newly synthesized bivalent ligands show a strong, predominantly NTS 1 R-mediated β-arrestin-2 recruitment at the D 2 R/NTS 1 R-coexpressing cells. G protein-coupled receptors (GPCRs) are involved in key signalling pathways and represent important targets for the treatment of neurological and psychiatric disorders. Here, the authors describe powerful bivalent ligands that efficiently bind to therapeutically relevant GPCR heterodimers