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Vidal-Mosquera M.,Institute Of Quimica Avanc Ada Of Catalonia Iqac Csic | Fernandez-Carvajal A.,University Miguel Hernandez | Moure A.,Institute Of Quimica Avanc Ada Of Catalonia Iqac Csic | Valente P.,University Miguel Hernandez | And 5 more authors.
Journal of Medicinal Chemistry | Year: 2011

The thermosensory transient receptor potential vanilloid 1 channel (TRPV1) is a polymodal receptor activated by physical and chemical stimuli. TRPV1 activity is drastically potentiated by proinflammatory agents released upon tissue damage. Given the pivotal role of TRPV1 in human pain, there is pressing need for improved TRPV1 antagonists, the development of which will require identification of new pharmacophore scaffolds. Uncompetitive antagonists acting as open-channel blockers might serve as activity-dependent blockers that preferentially modulate the activity of overactive channels, thus displaying fewer side effects than their competitive counterparts. Herein we report the design, synthesis, biological evaluation, and SAR analysis of a family of triazine-based compounds acting as TRPV1 uncompetitive antagonists. We identified the triazine 8aA as a potent, pure antagonist that inhibits TRPV1 channel activity with nanomolar efficacy and strong voltage dependency. It represents a new class of activity-dependent TRPV1 antagonists and may serve as the basis for lead optimization in the development of new analgesics. © 2011 American Chemical Society.

Casasampere M.,Institute Of Quimica Avanc Ada Of Catalonia Iqac Csic | Camacho L.,Institute Of Quimica Avanc Ada Of Catalonia Iqac Csic | Cingolani F.,Institute Of Quimica Avanc Ada Of Catalonia Iqac Csic | Casas J.,Institute Of Quimica Avanc Ada Of Catalonia Iqac Csic | And 9 more authors.
Journal of Lipid Research | Year: 2015

Ceramidases catalyze the cleavage of ceramides into sphingosine and fatty acids. Previously, we reported on the use of the RBM14 fluorogenic ceramide analogs to determine acidic ceramidase activity. In this work, we investigated the activity of other amidohydrolases on RBM14 compounds. Both bacterial and human purified neutral ceramidases (NCs), as well as ectopically expressed mouse neutral ceramidase hydrolyzed RBM14 with different selectivity, depending on the N -acyl chain length. On the other hand, microsomes from alkaline ceramidase (ACER)3 knockdown cells were less competent at hydrolyzing RBM14C12, RBM12C14, and RBM14C16 than controls, while microsomes from ACER2 and ACER3 overexpressing cells showed no activity toward the RBM14 substrates. Conversely, N -acylethanolamine-hydrolyzing acid amidase (NAAA) overexpressing cells hydrolyzed RBM14C14 and RBM14C16 at acidic pH. Overall, NC, ACER3, and, to a lesser extent, NAAA hydrolyze fluorogenic RBM14 compounds. Although the selectivity of the substrates toward ceramidases can be modulated by the length of the N -acyl chain, none of them was specific for a particular enzyme. Despite the lack of specificity, these substrates should prove useful in library screening programs aimed at identifying potent and selective inhibitors for NC and ACER3. Copyright © 2015 by the American Society for Biochemistry and Molecular Biology, Inc.

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