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.

Role of central neurotensin in regulating feeding: Implications for the development and treatment of body weight disorders

“…It is possible that Nts acting via VTA NtsR1/D2R hetero-receptor complexes might exert NtsR1-mediated anorectic actions while blocking D2Rmediated psychomotor effects, without antagonizing D2R-mediated feeding control. The recent report of bivalent compounds that selectively target these NtsR1-D2R hetero-complexes while biasing for NtsR1-mediated signaling suggests future potential to selectively target this system in schizophrenic patients [109], which would, perhaps, blunt associated psychomotor effects while restraining feeding. Since weight gain is a major reason for medication noncompliance among schizophrenic patients, such drugs could be a useful alternative to stand-alone antipsychotics that produce this and other undesirable side effects.…”

Design, Synthesis, and Biological Evaluation of Bivalent Ligands Targeting Dopamine D2‐Like Receptors and the μ‐Opioid Receptor

“…Furthermore, bivalent ligand 12 d containing the shortest linker (18 atoms) showed excellent potency and high efficacy both in β‐arrestin 2 recruitment for μOR and MAPK‐P for D 4 R. On the other hand, ligation of D 2 ‐likeR ligands negatively influences the affinity for D 2 R and D 4 R when using [ 3 H]spiperone as the radioligand. However, a biphasic competition binding curve was observed for 12 d to D 4 R–μOR, which indicates a bivalent binding mode . Hence, compound 12 d could bridge the D 4 R–μOR heterodimer.…”

Allosteric Modulation of GPCRs: New Insights and Potential Utility for Treatment of Schizophrenia and Other CNS Disorders

“…Future studies will be needed to fully understand why some modulators that bind at a single protomer modulate mGlu 2/4 signaling, whereas others do not. In addition, other approaches using bivalent compounds to target heterodimer complexes have shown promise (Hubner et al, 2016), and it is possible that allosteric modulators could be developed that bind at the interface between the two subunits. Future work will be needed to determine the structural and molecular mechanisms through which allosteric modulation of heterodimer complexes occurs.…”