2. Academic Validation
  3. Heterobivalent Ligand for the Adenosine A2A-Dopamine D2 Receptor Heteromer

Heterobivalent Ligand for the Adenosine A2A-Dopamine D2 Receptor Heteromer

  • J Med Chem. 2022 Jan 13;65(1):616-632. doi: 10.1021/acs.jmedchem.1c01763.
Daniel Pulido 1 2,  Verònica Casadó-Anguera 3,  Marc Gómez-Autet 4,  Natàlia Llopart 3,  Estefanía Moreno 3,  Nil Casajuana-Martin 4,  Sergi Ferré 5,  Leonardo Pardo 4,  Vicent Casadó 3,  Miriam Royo 1 2
Affiliations

Affiliations

  • 1 Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 08034 Barcelona, Spain.
  • 2 Department of Surfactants and Nanobiotechnology, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), 08034 Barcelona, Spain.
  • 3 Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028 Barcelona, Spain.
  • 4 Laboratori de Medicina Computacional, Unitat de Bioestadística, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
  • 5 Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224, United States.
PMID: 34982555 DOI: 10.1021/acs.jmedchem.1c01763
Abstract

A G protein-coupled receptor heteromer that fulfills the established criteria for its existence in vivo is the complex between adenosine A2A (A2AR) and dopamine D2 (D2R) receptors. Here, we have designed and synthesized heterobivalent ligands for the A2AR-D2R heteromer with various spacer lengths. The indispensable simultaneous binding of these ligands to the two different orthosteric sites of the heteromer has been evaluated by radioligand competition-binding assays in the absence and presence of specific Peptides that disrupt the formation of the heteromer, label-free dynamic mass redistribution assays in living cells, and molecular dynamic simulations. This combination of techniques has permitted us to identify compound 26 [KDB1 (A2AR) = 2.1 nM, KDB1 (D2R) = 0.13 nM], with a spacer length of 43-atoms, as a true bivalent ligand that simultaneously binds to the two different orthosteric sites. Moreover, bioluminescence resonance energy transfer experiments indicate that 26 favors the stabilization of the A2AR-D2R heteromer.

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