Triazine-Based Vanilloid 1 Receptor Open Channel Blockers: Design, Synthesis, Evaluation, and SAR Analysis

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 pres...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2011-11, Vol.54 (21), p.7441-7452
Main Authors: Vidal-Mosquera, Miquel, Fernández-Carvajal, Asia, Moure, Alejandra, Valente, Pierluigi, Planells-Cases, Rosa, González-Ros, José M, Bujons, Jordi, Ferrer-Montiel, Antonio, Messeguer, Angel
Format: Article
Language:English
Subjects:
Analgesics - chemical synthesis
Analgesics - chemistry
Analgesics - pharmacology
Animals
Binding Sites
Drug Design
Female
Oocytes - drug effects
Oocytes - physiology
Patch-Clamp Techniques
Rats
Recombinant Proteins - antagonists & inhibitors
Structure-Activity Relationship
Triazines - chemical synthesis
Triazines - chemistry
Triazines - pharmacology
TRPV Cation Channels - antagonists & inhibitors
Xenopus
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm200981s