title: LASSBio-881: an N-acylhydrazone transient receptor potential vanilloid subfamily type 1 antagonist orally effective against the hypernociception induced by capsaicin or partial sciatic ligation.
abstract: OBJECTIVE
  Compound LASSBio-881 is an orally effective antinociceptive that binds to cannabinoid receptors and is active mainly on the neurogenic component of pain models. We investigated whether transient receptor potential vanilloid subfamily type 1 (TRPV1) channels are involved in the effects of LASSBio-881.
  
  
  METHODS
  Modulation of capsaicin (CAP)- and low pH-induced currents was evaluated in TRPV1-expressing Xenopus oocytes. In vivo effects were evaluated in CAP-induced acute and inflammatory changes in nociception, as well as in partial sciatic ligation-induced thermal hypernociception.
  
  
  RESULTS
  LASSBio-881 inhibited TRPV1 currents elicited by CAP with an IC(50) of 14 microM, and inhibited proton-gated currents by 70% at 20 microM. Functional interaction with CAP was surmountable. Locally applied LASSBio-881 decreased time spent in CAP-elicited nocifensive behaviour by 30%, and given orally it reduced measures of CAP- or carrageenan-evoked thermal hypernociception by 60 and 40% respectively. In addition, LASSBio-881 decreased the paw withdrawal responses to thermal stimuli of animals with sciatic neuropathy 7-11 days after nerve ligation, at a dose of 300 micromol*kg(-1)*day(-1) p.o. At this dose, hyperthermia was not observed within 4 h following oral administration.
  
  
  CONCLUSIONS
  LASSBio-881 is a TRPV1 antagonist that apparently competes with CAP. Accordingly, LASSBio- 881 inhibited nociception in models of acute, inflammatory and neuropathic pain presumed to involve TRPV1 signalling. These in vivo actions were not hindered by hyperthermia, a common side effect of other TRPV1 antagonists. We propose that the antinociceptive properties of LASSBio-881 are due to TRPV1 antagonism, although other molecular interactions may contribute to the effects of this multi-target drug candidate.
authors.affiliation: Universidade Federal do Rio de Janeiro, RJ, Brazil.
authors.forename: J L M
authors.initials: JL
authors.lastname: Tributino
authors.forename: M L H
authors.initials: ML
authors.lastname: Santos
authors.forename: C M
authors.initials: CM
authors.lastname: Mesquita
authors.forename: C K F
authors.initials: CK
authors.lastname: Lima
authors.forename: L L
authors.initials: LL
authors.lastname: Silva
authors.forename: R C
authors.initials: RC
authors.lastname: Maia
authors.forename: C D
authors.initials: CD
authors.lastname: Duarte
authors.forename: E J
authors.initials: EJ
authors.lastname: Barreiro
authors.forename: C A M
authors.initials: CA
authors.lastname: Fraga
authors.forename: N G
authors.initials: NG
authors.lastname: Castro
authors.forename: A L P
authors.initials: AL
authors.lastname: Miranda
authors.forename: M Z P
authors.initials: MZ
authors.lastname: Guimaraes
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology*; D005260:Female; D006834:Hydrazines / Q000008:administration & dosage / Q000627:therapeutic use*; D051379:Mice; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy* / Q000209:etiology; D051381:Rats; D017208:Rats, Wistar; D012584:Sciatic Nerve / Q000601:surgery*; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*; D014982:Xenopus laevis
chemical_list: D000700:Analgesics; D006834:Hydrazines; C518927:LASSBio-881; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D002211:Capsaicin
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