化学
腺苷A2A受体
多巴胺受体D2
G蛋白偶联受体
配体(生物化学)
立体化学
生物物理学
腺苷受体
受体
生物化学
兴奋剂
生物
作者
Daniel Pulido,Verònica Casadó-Anguera,Marc Gómez‐Autet,Natàlia Llopart,Estefanía Moreno,Nil Casajuana‐Martin,Sergi Ferré,Leonardo Pardo,Vicent Casadó,Míriam Royo
标识
DOI:10.1021/acs.jmedchem.1c01763
摘要
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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