title: Triazine-based vanilloid 1 receptor open channel blockers: design, synthesis, evaluation, and SAR analysis.
abstract: 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.
authors.affiliation: Department of Chemical and Biomolecular Nanotechnology, Institut de Química Avançada de Catalunya, Barcelona, Spain.
authors.forename: Miquel
authors.initials: M
authors.lastname: Vidal-Mosquera
authors.forename: Asia
authors.initials: A
authors.lastname: Fernández-Carvajal
authors.forename: Alejandra
authors.initials: A
authors.lastname: Moure
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Valente
authors.forename: Rosa
authors.initials: R
authors.lastname: Planells-Cases
authors.forename: José M
authors.initials: JM
authors.lastname: González-Ros
authors.forename: Jordi
authors.initials: J
authors.lastname: Bujons
authors.forename: Antonio
authors.initials: A
authors.lastname: Ferrer-Montiel
authors.forename: Angel
authors.initials: A
authors.lastname: Messeguer
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D015195:Drug Design; D005260:Female; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014981:Xenopus
chemical_list: C569668:2,4-bis(4'-fluorophenethylamino)-6-(3'-(N,N-dimethylamino)propylamino)-1,3,5-triazine; D000700:Analgesics; D011994:Recombinant Proteins; D050916:TRPV Cation Channels; D014227:Triazines; C493922:Trpv1 protein, rat