Heterobivalent Ligand for the Adenosine A2A-Dopamine D2 Receptor Heteromer

被引:14
作者
Pulido, Daniel [1 ,2 ]
Casado-Anguera, Veronica [3 ]
Gomez-Autet, Marc [4 ]
Llopart, Natalia [3 ]
Moreno, Estefania [3 ]
Casajuana-Martin, Nil [4 ]
Ferre, Sergi [5 ]
Pardo, Leonardo [4 ]
Casado, Vicent [3 ]
Royo, Miriam [1 ,2 ]
机构
[1] Biomed Res Networking Ctr Bioengn Biomat & Nanome, Barcelona 08034, Spain
[2] Inst Adv Chem Catalonia IQAC, Dept Surfactants & Nanobiotechnol, CSIC, Barcelona 08034, Spain
[3] Univ Barcelona, Inst Biomed Univ Barcelona IBUB, Fac Biol, Dept Biochem & Mol Biomed, Barcelona 08028, Spain
[4] Univ Autonoma Barcelona, Fac Med, Unitat Bioestadist, Lab Med Computac, Bellaterra 08193, Spain
[5] NIDA, Integrat Neurobiol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA
关键词
PROTEIN-COUPLED RECEPTORS; BIVALENT LIGANDS; RECOGNITION PATHWAY; BITOPIC LIGANDS; A(2A) RECEPTOR; GPCR DIMERS; BINDING; DESIGN; FLUORESCENCE; DIMERIZATION;
D O I
10.1021/acs.jmedchem.1c01763
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A G protein-coupled receptor heteromer that fulfills the established criteria for its existence in vivo is the complex between adenosine A(2A) (A(2A)R) and dopamine D-2 (D2R) receptors. Here, we have designed and synthesized heterobivalent ligands for the A(2A)R-D-2R 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 [K-DB1 (A(2A)R) = 2.1 nM, K-DB1 (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 A(2A)R-D2R heteromer.
引用
收藏
页码:616 / 632
页数:17
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