Research article summary (published 22 Sep 2009):

Adenosine A2A receptor-antagonist/dopamine D2 receptor-agonist bivalent ligands as pharmacological tools to detect A2A-D2 receptor heteromers.

Full Abstract

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.

Author information

Author/s: Soriano, Aroa (A); 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);

Affiliation: 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.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: Journal of medicinal chemistry (J Med Chem), published in United States. (Language: eng)

Reference: 2009-Sep; vol 52 (issue 18) : pp 5590-602

Dates: Created 2009/09/17; Completed 2009/10/14;

PMID: 19711895, status: MEDLINE (last retrieval date: 10/14/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Adenosine - metabolism Amino Acids - chemistry Animals Cell Line Cyclic AMP - biosynthesis Drug Design Gene Expression Regulation Humans Intracellular Space - drug effects; metabolism Ligands Mice

Mice Neostriatum - metabolism Nylons - chemistry Polyethylene Glycols - chemistry Protein Multimerization Protein Structure, Quaternary Radioligand Assay Receptor, Adenosine A2A - antagonists & inhibitors; chemistry; metabolism Receptors, Dopamine - metabolism Receptors, Dopamine D2 - agonists; chemistry; metabolism Small Molecule Libraries - chemical synthesis; chemistry; pharmacology

Associated Chemicals: Amino Acids (0) ; Ligands (0) ; Nylons (0) ; Polyethylene Glycols (0) ; Receptor, Adenosine A2A (0) ; Receptors, Dopamine (0) ; Receptors, Dopamine D2 (0) ; Small Molecule Libraries (0) ; Adenosine (58-61-7) ; Cyclic AMP (60-92-4)

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