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

Autor: Asia Fernández-Carvajal, Jordi Bujons, Angel Messeguer, Miquel Vidal-Mosquera, Antonio Ferrer-Montiel, Rosa Planells-Cases, Alejandra Moure, José M. González-Ros, Pierluigi Valente
Rok vydání: 2011
Předmět:
Patch-Clamp Techniques
Xenopus
TRPV1
TRPV Cation Channels
Pharmacology
Proinflammatory cytokine
chemical synthesis/chemistry/pharmacology
Structure-Activity Relationship
Transient receptor potential channel
chemistry.chemical_compound
Drug Discovery
Analgesics
chemical synthesis/chemistry/pharmacology
Animals
Binding Sites
Drug Design
Female
Oocytes
drug effects/physiology
Patch-Clamp Techniques
Rats
Recombinant Proteins
antagonists /&/ inhibitors
Structure-Activity Relationship
TRPV Cation Channels
antagonists /&/ inhibitors
Triazines
chemical synthesis/chemistry/pharmacology
Xenopus
Animals
Receptor
Triazine
antagonists /&/ inhibitors
Binding Sites
Triazines
musculoskeletal
neural
and ocular physiology
Antagonist
Recombinant Proteins
Rats
drug effects/physiology
nervous system
chemistry
Design synthesis
Drug Design
Oocytes
Molecular Medicine
Female
lipids (amino acids
peptides
and proteins)
Pharmacophore
Zdroj: Digital.CSIC. Repositorio Institucional del CSIC
instname
JOURNAL OF MEDICINAL CHEMISTRY
r-CIPF. Repositorio Institucional Producción Científica del Centro de Investigación Principe Felipe (CIPF)
r-CIPF: Repositorio Institucional Producción Científica del Centro de Investigación Principe Felipe (CIPF)
Centro de Investigación Principe Felipe (CIPF)
ISSN: 1520-4804
0022-2623
DOI: 10.1021/jm200981s
Popis: 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.
This work was supported by grants from Spanish Ministry of Science and Innovation (Grant SAF2008-00048 to A.M., Grant BFU2009-08346 to A.F.-M., CONSOLIDER-INGENIO 2010 (Grant CSD2008-00005) to A.F.-M., J.M.G.-R., and A.M.), from Fundació La Marató de TV3 (to A.F.-M. and A.M.), and from PROMETEO/2010/046 from the GVA to A.F.-M.
Databáze: OpenAIRE
Externí odkaz: