Structure-guided development of heterodimer-selective GPCR ligands

• DOI: 10.1038/ncomms12298
• Publication Date: 2016-07-26T10:15:03Z
• Authors: Harald Hübner; Tamara Schellhorn; Marie Gienger; Carolin Schaab; Jonas Kaindl; Laurin Leeb; Timothy Clark; Dorothee Möller; Peter Gmeiner
• Keywords: Bivalent (engine); Linker; Neurotensin receptor

Abstract Crystal structures of G protein-coupled receptor (GPCR) ligand complexes allow a rational design novel molecular probes and drugs. Here we report the structure-guided design, chemical synthesis biological investigations bivalent ligands for dopamine D 2 receptor/neurotensin NTS 1 (D R/NTS R) heterodimers. The compounds types 1–3 consist three different R pharmacophores bound to an affinity-generating lipophilic appendage, polyethylene glycol-based linker agonist NT(8-13). show binding affinity in picomolar range cells coexpressing both GPCRs unprecedented selectivity (up orders magnitude), compared with that only express Rs. A functional switch is observed 3b,c inhibiting cAMP formation singly expressing Rs but stimulating accumulation R-coexpressing cells. Moreover, newly synthesized strong, predominantly R-mediated β-arrestin-2 recruitment at