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Molecules 2017, 22(3), 366;

Synthesis and Characterization of a New Bivalent Ligand Combining Caffeine and Docosahexaenoic Acid

Unitat de Farmacologia, Departament Patologia i Terapèutica Experimental, Facultat de Medicina, IDIBELL-Universitat de Barcelona, L’Hospitalet de Llobregat, 08907 Barcelona, Spain
Institut de Neurociències, Universitat de Barcelona, 08035 Barcelona, Spain
Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CIQUS), Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
Departamento de Química Orgánica, Facultad de Farmacia, Universidade de Santiago de Compostela, Santiago de Compostela, 15782 Santiago de Compostela, Spain
Departament de Bioquímica i Biomedicina, Universitat de Barcelona, 08028 Barcelona, Spain
Authors to whom correspondence should be addressed.
Academic Editor: Derek J. McPhee
Received: 9 January 2017 / Accepted: 23 February 2017 / Published: 27 February 2017
(This article belongs to the Special Issue Adenosine Receptors)
Full-Text   |   PDF [1077 KB, uploaded 2 March 2017]   |  


Caffeine is a promising drug for the management of neurodegenerative diseases such as Parkinson’s disease (PD), demonstrating neuroprotective properties that have been attributed to its interaction with the basal ganglia adenosine A2A receptor (A2AR). However, the doses needed to exert these neuroprotective effects may be too high. Thus, it is important to design novel approaches that selectively deliver this natural compound to the desired target. Docosahexaenoic acid (DHA) is the major omega-3 fatty acid in the brain and can act as a specific carrier of caffeine. Furthermore, DHA displays properties that may lead to its use as a neuroprotective agent. In the present study, we constructed a novel bivalent ligand covalently linking caffeine and DHA and assessed its pharmacological activity and safety profile in a simple cellular model. Interestingly, the new bivalent ligand presented higher potency as an A2AR inverse agonist than caffeine alone. We also determined the range of concentrations inducing toxicity both in a heterologous system and in primary striatal cultures. The novel strategy presented here of attaching DHA to caffeine may enable increased effects of the drug at desired sites, which could be of interest for the treatment of PD. View Full-Text
Keywords: adenosine A2A receptor; caffeine; docosahexaenoic acid (DHA); inverse agonism adenosine A2A receptor; caffeine; docosahexaenoic acid (DHA); inverse agonism

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Fernández-Dueñas, V.; Azuaje, J.; Morató, X.; Cordobilla, B.; Domingo, J.C.; Sotelo, E.; Ciruela, F. Synthesis and Characterization of a New Bivalent Ligand Combining Caffeine and Docosahexaenoic Acid. Molecules 2017, 22, 366.

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