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Vazquez-Carrera M.,Unitat de Farmacologia
Drugs of the Future | Year: 2012

GFT-505 is a first-in-class dual peroxisome proliferator-activated receptor PPAR-α/δ agonist being developed by Genfit for the potential treatment of atherosclerosis, dyslipidemia, type 2 diabetes, insulin resistance, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Preclinical and phase II trials have demonstrated that GFT-505 reduces plasma triglyceride levels, increases HDL cholesterol and improves insulin sensitivity and markers of liver dysfunction associated with NAFLD/NASH. No significant toxicological or safety concerns have been identified in studies in animals and humans. The reported efficacy and safety data for GFT-505 currently available support the continued development of the compound. At the time of publication, phase III trials were under way, but no results have been reported. The use of a dual PPAR- α/δ agonist may provide unique benefits for the prevention and treatment of several risk factors (insulin resistance, type 2 diabetes, atherogenic dyslipidemia and NAFLD/NASH) of cardiovascular diseases and metabolic syndrome. Copyright © 2012 Prous Science, S.A.U. or its licensors. All rights reserved.


Borroto-Escuela D.O.,Karolinska Institutet | Marcellino D.,Karolinska Institutet | Narvaez M.,University of Malaga | Flajolet M.,Rockefeller University | And 4 more authors.
Biochemical and Biophysical Research Communications | Year: 2010

Evidence exists that the adenosine receptor A2AR and the dopamine receptor D2R form constitutive heteromers in living cells. Mass spectrometry and pull-down data showed that an arginine-rich domain of the D2R third intracellular loop binds via electrostatic interactions to a specific motif of the A2AR C-terminal tail. It has been indicated that the phosphorylated serine 374 might represent an important residue in this motif. In the present study, it was found that a point mutation of serine 374 to alanine reduced the A2AR ability to interact with D2R. Also, this point mutation abolished the A2AR-mediated inhibition of both the D2R high affinity agonist binding and signaling. These results point to a key role of serine 374 in the A2AR-D2R interface. All together these results indicate that by targeting A2AR serine 374 it will be possible to allosterically modulate A2AR-D2R function, thus representing a new approach for therapeutically modulate D2R function. © 2010 Elsevier Inc.


Borroto-Escuela D.O.,Polytechnic University of Catalonia | Borroto-Escuela D.O.,Karolinska Institutet | Romero-Fernandez W.,Polytechnic University of Catalonia | Garcia-Negredo G.,Unitat de Farmacologia | And 4 more authors.
Cellular Physiology and Biochemistry | Year: 2011

Acetylcholine challenge produces M 3 muscarinic acetylcholine receptor activation and accessory/scaffold proteins recruitment into a signalsome complex. The dynamics of such a complex is not well understood but a conserved NPxxY motif located within transmembrane 7 and juxtamembrane helix 8 of the receptor was found to modulate G protein activation. Here by means of receptor mutagenesis we unravel the role of the conserved M 3 muscarinic acetylcholine receptor NPxxY motif on ligand binding, signaling and multiprotein complex formation. Interestingly, while a N7.49D receptor mutant showed normal ligand binding properties a N7.49A mutant had reduced antagonist binding and increased affinity for carbachol. Also, besides this last mutant was able to physically couple to Gα q/11 after carbachol challenge it was neither capable to activate phospholipase C nor phospholipase D. On the other hand, we demonstrated that the Asn-7.49 is important for the interaction between M 3R and ARF1 and also for the formation of the ARF/Rho/β γ signaling complex, a complex that might determine the rapid activation and desensitization of PLD. Overall, these results indicate that the NPxxY motif of the M 3 muscarinic acetylcholine receptor acts as key conformational switch for receptor signaling and multiprotein complex formation. Copyright © 2011 S. Karger AG, Basel.


Fernandez-Duenas V.,Unitat de Farmacologia | Gomez-Soler M.,Unitat de Farmacologia | Morato X.,Unitat de Farmacologia | Nunez F.,Unitat de Farmacologia | And 5 more authors.
Neurochemistry International | Year: 2013

The molecular interaction between adenosine A2A and dopamine D2 receptors (A2ARs and D2Rs, respectively) within an oligomeric complex has been postulated to play a pivotal role in the adenosine-dopamine interplay in the central nervous system, in both normal and pathological conditions (e.g. Parkinson's disease). While the effects of A 2AR challenge on D2R functioning have been largely studied, the reverse condition is still unexplored, a fact that might have impact in therapeutics. Here, we aimed to examine in a real-time mode the D 2R-mediated allosteric modulation of A2AR binding when an A2AR/D2R oligomer is established. Thus, we synthesized fluorescent A2AR agonists and evaluated, by means of a flow cytometry homogeneous no-wash assay and a real-time fluorescence resonance energy transfer (FRET)-based approach, the effects on A2AR binding of distinct antiparkinsonian drugs in current clinical use (i.e. pramipexole, rotigotine and apomorphine). Our results provided evidence for the existence of a differential D2R-mediated negative allosteric modulation on A 2AR agonist binding that was oligomer-formation dependent, and with apomorphine being the best antiparkinsonian drug attenuating A2AR agonist binding. Overall, the here-developed methods were found valid to explore the ability of drugs acting on D2Rs to modulate A2AR binding, thus serving to facilitate the preliminary selection of D 2R-like candidate drugs in the management of Parkinson's disease. © 2013 Elsevier Ltd. All rights reserved.


Ciruela F.,Unitat de Farmacologia | Fernandez-Duenas V.,Unitat de Farmacologia | Llorente J.,Unitat de Farmacologia | Borroto-Escuela D.,Karolinska Institutet | And 6 more authors.
Brain Research | Year: 2012

The control of glutamatergic corticostriatal transmission is essential for the induction and expression of plasticity mechanisms in the striatum, a phenomenon thickly regulated by G protein-coupled receptors (GPCRs). Interestingly, in addition to dopamine receptors, adenosine and metabotropic glutamate receptors also play a key role in striatal functioning. The existence of a supramolecular organization (i.e. oligomer) containing dopamine, adenosine and metabotropic glutamate receptors in the striatal neurons is now being widely accepted by the scientific community. Indeed, these oligomers may enhance the diversity and performance by which extracellular striatal signals are transferred to the G-proteins in the process of receptor transduction, and also may allow unpredictable receptor-receptor allosteric regulations. Overall, here we want to review how formations of adenosine, dopamine and metabotropic glutamate receptors-containing oligomers impinge into striatal functioning in both normal and pathological conditions. This article is part of a Special Issue entitled: Brain Integration. © 2012 Elsevier B.V. All rights reserved.

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