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

Trincavelli ML, Daniele S, Orlandini E, Navarro G, Casadó V, Giacomelli C, Nencetti S, Nuti E, Maccia M, Hübner H, Gmeiner P, Rossello A, LLuís C, Martini C (2012)

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Publication Language: English

Publication Type: Journal article, Original article

Publication year: 2012

Journal

Original Authors: Trincavelli M.L., Daniele S., Orlandini E., Navarro G., Casado V., Giacomelli C., Nencetti S., Nuti E., Macchia M., Huebner H., Gmeiner P., Rossello A., Lluis C., Martini C.

Publisher: Elsevier

Book Volume: 24

Pages Range: 951-960

Journal Issue: 4

DOI: 10.1016/j.cellsig.2011.12.018

Abstract

The structural and functional interaction between D dopamine receptor (DR) and A 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 DDR induces a significant negative regulation of AAR-mediated responses, whereas few data are at now available about the regulation of AAR by DDR agonists at receptor recognition site. In this work we confirmed that in AAR/DDR co-transfected cells, these receptors exist as homo- and hetero-dimers. The classical DDR agonists were able to negatively modulate both AAR affinity and functionality. These effects occurred even if any significant changes in AAR/DDR energy transfer interaction could be detected in BRET experiments.Since the development of new molecules able to target A/D 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 DDR and modulator of A-D receptor dimer. This compound was able to negatively modulate AAR binding properties and functional responsiveness in a manner comparable to classical DR agonists. In contrast to classical agonists, compound 1 led to conformational changes in the quaternary structure in DDR homomers and heteromers and induced AAR/DDR 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 AAR/D DR heteromers. © 2011 Elsevier Inc.

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APA:

Trincavelli, M.L., Daniele, S., Orlandini, E., Navarro, G., Casadó, V., Giacomelli, C.,... Martini, C. (2012). A new D2 dopamine receptor agonist allosterically modulates A2A adenosine receptor signalling by interacting with the A2A/D2 receptor heteromer. Cellular Signalling, 24(4), 951-960. https://doi.org/10.1016/j.cellsig.2011.12.018

MLA:

Trincavelli, Maria Letizia, et al. "A new D2 dopamine receptor agonist allosterically modulates A2A adenosine receptor signalling by interacting with the A2A/D2 receptor heteromer." Cellular Signalling 24.4 (2012): 951-960.

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