Heterobivalent Ligand for the Adenosine A2A-Dopamine D2Receptor Heteromer

Daniel Pulido, Verònica Casadó-Anguera, Marc Gómez-Autet, Natàlia Llopart, Estefanía Moreno, Nil Casajuana-Martin, Sergi Ferré, Leonardo Pardo*, Vicent Casadó*, Miriam Royo*

*Autor correspondiente de este trabajo

Producción científica: Contribución a una revistaArtículoInvestigaciónrevisión exhaustiva

13 Citas (Scopus)

Resumen

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.
Idioma originalInglés
Páginas (desde-hasta)616-632
Número de páginas17
PublicaciónJournal of Medicinal Chemistry
Volumen65
N.º1
DOI
EstadoPublicada - 13 ene 2022

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