title: LASSBio-1135: a dual TRPV1 antagonist and anti-TNF-alpha compound orally effective in models of inflammatory and neuropathic pain.
abstract: LASSBio-1135 is an imidazo[1,2-a]pyridine derivative with high efficacy in screening models of nociception and inflammation, presumed as a weak COX-2 inhibitor. In order to tease out its mechanism of action, we investigated others possible target for LASSBio-1135, such as TNF-α and TRPV1, to better characterize it as a multitarget compound useful in the treatment of chronic pain. TRPV1 modulation was assessed in TRPV1-expressing Xenopus oocytes against capsaicin and low pH-induced current. Modulation of TNF-α production was evaluated in culture of macrophages stimulated with LPS. In vivo efficacy of LASSBio-1135 was investigated in carrageenan and partial sciatic ligation-induced thermal hyperalgesia and mechanical allodynia. Corroborating its previous demonstration of efficacy in a model of capsaicin-induced hyperalgesia, LASSBio-1135 blocks capsaicin-elicited currents in a non-competitive way with an IC50 of 580 nM as well as low pH-induced current at 50 µM. As an additional action, LASSBio-1135 inhibited TNF-α release in these cells stimulated by LPS with an IC50 of 546 nM by reducing p38 MAPK phosphorilation. Oral administration of 100 µmol x Kg(-1) LASSBio-1135 markedly reduced thermal hyperalgesia induced by carrageenan, however at 10 µmol x Kg(-1) only a partial reduction was observed at the 4th h. Neutrophil recruitment and TNF-α production after carrageenan stimulus was also inhibited by the treatment with LASSBio-1135. Modulating TRPV1 and TNF-α production, two key therapeutic targets of neuropathic pain, 100 µmol x Kg(-1) LASSBio-1135 was orally efficacious in reversing thermal hyperalgesia and mechanical allodynia produced by partial sciatic ligation 7-11 days after surgery without provoking hyperthermia, a common side effect of TRPV1 antagonists. In conclusion LASSBio-1135, besides being a weak COX-2 inhibitor, is a non-competitive TRPV1 antagonist and a TNF-α inhibitor. As a multitarget compound, LASSBio-1135 is orally efficacious in a model of neuropathic pain without presenting hyperthermia.
authors.affiliation: Laboratório de Estudos em Farmacologia Experimental (LEFEx), Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Cleverton K F
authors.initials: CK
authors.lastname: Lima
authors.affiliation: Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Rafael M
authors.initials: RM
authors.lastname: Silva
authors.affiliation: Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Renata B
authors.initials: RB
authors.lastname: Lacerda
authors.affiliation: Laboratório de Estudos em Farmacologia Experimental (LEFEx), Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Bruna L R
authors.initials: BL
authors.lastname: Santos
authors.affiliation: Laboratório de Estudos em Farmacologia Experimental (LEFEx), Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Rafaela V
authors.initials: RV
authors.lastname: Silva
authors.affiliation: Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Luciana S
authors.initials: LS
authors.lastname: Amaral
authors.affiliation: Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Luís E M
authors.initials: LE
authors.lastname: Quintas
authors.affiliation: Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Carlos A M
authors.initials: CA
authors.lastname: Fraga
authors.affiliation: Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Eliezer J
authors.initials: EJ
authors.lastname: Barreiro
authors.affiliation: Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Marília Z P
authors.initials: MZ
authors.lastname: Guimaraes
authors.affiliation: Laboratório de Estudos em Farmacologia Experimental (LEFEx), Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Ana L P
authors.initials: AL
authors.lastname: Miranda
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D002351:Carrageenan; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006863:Hydrogen-Ion Concentration; D006930:Hyperalgesia / Q000150:complications / Q000188:drug therapy; D007093:Imidazoles / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D007249:Inflammation / Q000150:complications / Q000188:drug therapy*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008807:Mice, Inbred BALB C; D009437:Neuralgia / Q000150:complications / Q000188:drug therapy*; D020556:Neutrophil Infiltration / Q000187:drug effects; D009865:Oocytes / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D014982:Xenopus laevis; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C000599050:2-phenyl-N-(2-pyridinyl)imidazo(1,2-a)pyridin-3-amine; D007093:Imidazoles; D011725:Pyridines; D050916:TRPV Cation Channels; D014409:Tumor Necrosis Factor-alpha; D002351:Carrageenan; D048051:p38 Mitogen-Activated Protein Kinases; D002211:Capsaicin