Adenosine A2A receptor-antagonist/dopamine D2 receptor-agonist bivalent ligands as pharmacological tools to detect A2A-D2 receptor heteromers.
Adenosine A(2A) (A(2A)R) and dopamine D(2) (D(2)R) receptors mediate the antagonism between adenosinergic and dopaminergic transmission in striatopallidal GABAergic neurons and are pharmacological targets for the treatment of Parkinson's disease. Here, a family of heterobivalent ligands containing a D(2)R agonist and an A(2A)R antagonist linked through a spacer of variable size was designed and synthesized to study A(2A)R-D(2)R heteromers. Bivalent ligands with shorter linkers bound to D(2)R or A(2A)R with higher affinity than the corresponding monovalent controls in membranes from brain striatum and from cells coexpressing both receptors. In contrast, no differences in affinity of bivalent versus monovalent ligands were detected in experiments using membranes from cells expressing only one receptor. These findings indicate the existence of A(2A)R-D(2)R heteromers and of a simultaneous interaction of heterobivalent ligands with both receptors. The cooperative effect derived from the simultaneous interaction suggests the occurrence of A(2A)R-D(2)R heteromers in cotransfected cells and in brain striatum. The dopamine/adenosine bivalent action could constitute a novel concept in Parkinson's disease pharmacotherapy.
Soriano
Aroa
A
Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), and Department of Biochemistry and Molecular Biology, University of Barcelona, Avenida Diagonal 645, E-08028 Barcelona, Spain.
Ventura
Ruben
R
Molero
Anabel
A
Hoen
Rob
R
Casadó
Vicent
V
Cortés
Antoni
A
Fanelli
Francesca
F
Albericio
Fernando
F
Lluís
Carmen
C
Franco
Rafael
R
Royo
Miriam
M
D000241:Adenosine / Q000378:metabolism; D058917:Adenosine A2 Receptor Antagonists; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000096:biosynthesis; D015195:Drug Design; D005786:Gene Expression Regulation; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008024:Ligands; D051379:Mice; D017072:Neostriatum / Q000378:metabolism; D009757:Nylons / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D011869:Radioligand Assay; D043705:Receptor, Adenosine A2A / Q000737:chemistry / Q000378:metabolism*; D011954:Receptors, Dopamine / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D058917:Adenosine A2 Receptor Antagonists; D000596:Amino Acids; D008024:Ligands; D009757:Nylons; D043705:Receptor, Adenosine A2A; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D054852:Small Molecule Libraries; D011092:Polyethylene Glycols; D000242:Cyclic AMP; D000241:Adenosine