title: Design and characterization of a noncompetitive antagonist of the transient receptor potential vanilloid subunit 1 channel with in vivo analgesic and anti-inflammatory activity.
abstract: Vanilloid receptor subunit 1 (TRPV1) is an integrator of physical and chemical stimuli in the peripheral nervous system. This receptor plays a key role in the pathophysiology of inflammatory pain. Thus, the identification of receptor antagonists with analgesic and anti-inflammatory activity in vivo is an important goal of current neuropharmacology. Here, we report that [L-arginyl]-[N-[2,4-dichlorophenethyl]glycyl]-N-(2,4-dichlorophenethyl) glycinamide (H-Arg-15-15C) is a channel blocker that abrogates capsaicin and pH-evoked TRPV1 channel activity with submicromolar activity. Compound H-Arg-15-15C preferentially inhibits TRPV1, showing marginal block of other neuronal receptors. Compound H-Arg-15-15C acts as a noncompetitive capsaicin antagonist with modest voltage-dependent blockade activity. The compound inhibited capsaicin-evoked nerve activity in afferent fibers without affecting mechanically activated activity. Notably, administration of compound H-Arg-15-15C prevented the irritant activity of a local administration of capsaicin and formalin and reversed the thermal hyperalgesia evoked by injection of complete Freund's adjuvant. Furthermore, it attenuated carrageenan-induced paw inflammation. Compound H-Arg-15-15C specifically decreased inflammatory conditions without affecting normal nociception. Taken together, these findings demonstrate that compound H-Arg-15-15C is a channel blocker of TRPV1 with analgesic and anti-inflammatory activity in vivo at clinically useful doses and substantiate the tenet that TRPV1 plays an important role in the etiology of chronic inflammatory pain.
  
  
  CONCLUSIONS
  This study reports the design of a potent TRPV1 noncompetitive antagonist that exhibits anti-inflammatory and analgesic activity in preclinical models of acute and chronic pain. This compound is a lead for analgesic drug development.
authors.affiliation: Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, Alicante, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: García-Martínez
authors.forename: Asia
authors.initials: A
authors.lastname: Fernández-Carvajal
authors.forename: Belen
authors.initials: B
authors.lastname: Valenzuela
authors.forename: Ana
authors.initials: A
authors.lastname: Gomis
authors.forename: Wim
authors.initials: W
authors.lastname: Van Den Nest
authors.forename: Stefano
authors.initials: S
authors.lastname: Ferroni
authors.forename: Cristina
authors.initials: C
authors.lastname: Carreño
authors.forename: Carlos
authors.initials: C
authors.lastname: Belmonte
authors.forename: Antonio
authors.initials: A
authors.lastname: Ferrer-Montiel
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001120:Arginine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019556:COS Cells; D002211:Capsaicin / Q000037:antagonists & inhibitors; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology; D007473:Ion Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009619:Nociceptors / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D009865:Oocytes; D010146:Pain / Q000188:drug therapy* / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014981:Xenopus
chemical_list: C515378:(L-arginyl)-(N-(2,4-dichlorophenethyl)glycyl)-N-(2,4-dichlorophenethyl) glycinamide; D000700:Analgesics; D000893:Anti-Inflammatory Agents; D007473:Ion Channels; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C018556:glycine amide; D001120:Arginine; D002211:Capsaicin; D005998:Glycine