TY - JOUR
T1 - Heterobivalent Ligand for the Adenosine A2A-Dopamine D2Receptor Heteromer
AU - Pulido, Daniel
AU - Casadó-Anguera, Verònica
AU - Gómez-Autet, Marc
AU - Llopart, Natàlia
AU - Moreno, Estefanía
AU - Casajuana-Martin, Nil
AU - Ferré, Sergi
AU - Pardo, Leonardo
AU - Casadó, Vicent
AU - Royo, Miriam
N1 - Publisher Copyright:
© Copyright 2023 Elsevier B.V., All rights reserved.
PY - 2022/1/13
Y1 - 2022/1/13
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85122780146&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.1c01763
DO - 10.1021/acs.jmedchem.1c01763
M3 - Article
C2 - 34982555
AN - SCOPUS:85122780146
SN - 0022-2623
VL - 65
SP - 616
EP - 632
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 1
ER -