The structural and functional interaction between D₂ dopamine receptor (DR) and A(2A) adenosine receptor (AR) has suggested these two receptors as a pharmacological target in pathologies associated with dopamine dysfunction, such as Parkinson's disease. In transfected cell lines it has been demonstrated the activation of D₂DR induces a significant negative regulation of A(2A)AR-mediated responses, whereas few data are at now available about the regulation of A(2A)AR by D₂DR agonists at receptor recognition site. In this work we confirmed that in A(2A)AR/D₂DR co-transfected cells, these receptors exist as homo- and hetero-dimers. The classical D₂DR agonists were able to negatively modulate both A(2A)AR affinity and functionality. These effects occurred even if any significant changes in A(2A)AR/D₂DR energy transfer interaction could be detected in BRET experiments. Since the development of new molecules able to target A(2A)/D₂ dimers may represent an attractive tool for innovative pharmacological therapy, we also identified a new small molecule, 3-(3,4-dimethylphenyl)-1-(2-piperidin-1-yl)ethyl)piperidine (compound 1), full agonist of D₂DR and modulator of A(2A)-D₂ receptor dimer. This compound was able to negatively modulate A(2A)AR binding properties and functional responsiveness in a manner comparable to classical D₂R agonists. In contrast to classical agonists, compound 1 led to conformational changes in the quaternary structure in D₂DR homomers and heteromers and induced A(2A)AR/D₂DR co-internalization. These results suggest that compound 1 exerts a high control of the function of heteromers and could represent a starting point for the development of new drugs targeting A(2A)AR/D₂ DR heteromers.

A new D2 dopamine receptor agonist allosterically modulates A2A adenosine receptor signalling by interacting with the A2A/D2 receptor heteromer

TRINCAVELLI, MARIA LETIZIA;DANIELE, SIMONA;ORLANDINI, ELISABETTA;GIACOMELLI, CHIARA;NENCETTI, SUSANNA;NUTI, ELISA;MACCHIA, MARCO;ROSSELLO, ARMANDO;MARTINI, CLAUDIA
2012

Abstract

The structural and functional interaction between D₂ dopamine receptor (DR) and A(2A) adenosine receptor (AR) has suggested these two receptors as a pharmacological target in pathologies associated with dopamine dysfunction, such as Parkinson's disease. In transfected cell lines it has been demonstrated the activation of D₂DR induces a significant negative regulation of A(2A)AR-mediated responses, whereas few data are at now available about the regulation of A(2A)AR by D₂DR agonists at receptor recognition site. In this work we confirmed that in A(2A)AR/D₂DR co-transfected cells, these receptors exist as homo- and hetero-dimers. The classical D₂DR agonists were able to negatively modulate both A(2A)AR affinity and functionality. These effects occurred even if any significant changes in A(2A)AR/D₂DR energy transfer interaction could be detected in BRET experiments. Since the development of new molecules able to target A(2A)/D₂ dimers may represent an attractive tool for innovative pharmacological therapy, we also identified a new small molecule, 3-(3,4-dimethylphenyl)-1-(2-piperidin-1-yl)ethyl)piperidine (compound 1), full agonist of D₂DR and modulator of A(2A)-D₂ receptor dimer. This compound was able to negatively modulate A(2A)AR binding properties and functional responsiveness in a manner comparable to classical D₂R agonists. In contrast to classical agonists, compound 1 led to conformational changes in the quaternary structure in D₂DR homomers and heteromers and induced A(2A)AR/D₂DR co-internalization. These results suggest that compound 1 exerts a high control of the function of heteromers and could represent a starting point for the development of new drugs targeting A(2A)AR/D₂ DR heteromers.
Trincavelli, MARIA LETIZIA; Daniele, Simona; Orlandini, Elisabetta; Navarro, G.; Casado, V.; Giacomelli, Chiara; Nencetti, Susanna; Nuti, Elisa; Macchia, Marco; Huebner, H.; Gmeiner, P.; Rossello, Armando; Lluis, C.; Martini, Claudia
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11568/220731
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