title: A novel, potent, oral active and safe antinociceptive pyrazole targeting kappa opioid receptors.
abstract: Pyrazole compounds are an intriguing class of compounds with potential analgesic activity; however, their mechanism of action remains unknown. Thus, the goal of this study was to explore the antinociceptive potential, safety and mechanism of action of novel 1-pyrazole methyl ester derivatives, which were designed by molecular simplification, using in vivo and in vitro methods in mice. First, tree 1-pyrazole methyl ester derivatives (DMPE, MPFE, and MPCIE) were tested in the capsaicin test and all presented antinociceptive effect; however the MPClE (methyl 5-trichloromethyl-3-methyl-1H-pyrazole-1-carboxylate) was the most effective. Thus, we selected this compound to assess the effects and mechanisms in subsequent pain models. MPCIE produced antinociception when administered by oral, intraperitoneal, intrathecal and intraplantar routes and was effective in the capsaicin and the acetic acid-induced nociception tests. Moreover, this compound reduced the hyperalgesia in diverse clinically-relevant pain models, including postoperative, inflammatory, and neuropathic nociception in mice. The antinociception produced by orally administered MPClE was mediated by κ-opioid receptors, since these effects were prevented by systemically pre-treatment with naloxone and the κ-opioid receptor antagonist nor-binaltorphimine. Moreover, MPCIE prevented binding of the κ-opioid ligand [(3)H]-CI-977 in vitro (IC₅₀ of 0.68 (0.32-1.4) μM), but not the TRPV1 ([(3)H]-resiniferatoxin) or the α₂-adrenoreceptor ([(3)H]-idazoxan) binding. Regarding the drug-induced side effects, oral administration of MPClE did not produce sedation, constipation or motor impairment at its active dose. In addition, MPCIE was readily absorbed after oral administration. Taken together, these results demonstrate that MPClE is a novel, potent, orally active and safe analgesic drug that targets κ-opioid receptors.
authors.affiliation: Graduate Program in Biological Sciences - Toxicological Biochemistry, Department of Chemistry, Federal University of Santa Maria, 97105-900 Santa Maria, RS, Brazil.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Trevisan
authors.forename: Mateus F
authors.initials: MF
authors.lastname: Rossato
authors.forename: Cristiani I B
authors.initials: CI
authors.lastname: Walker
authors.forename: Sara M
authors.initials: SM
authors.lastname: Oliveira
authors.forename: Fernanda
authors.initials: F
authors.lastname: Rosa
authors.forename: Raquel
authors.initials: R
authors.lastname: Tonello
authors.forename: Cássia R
authors.initials: CR
authors.lastname: Silva
authors.forename: Pablo
authors.initials: P
authors.lastname: Machado
authors.forename: Aline A
authors.initials: AA
authors.lastname: Boligon
authors.forename: Marcos A P
authors.initials: MA
authors.lastname: Martins
authors.forename: Nilo
authors.initials: N
authors.lastname: Zanatta
authors.forename: Hélio G
authors.initials: HG
authors.lastname: Bonacorso
authors.forename: Margareth L
authors.initials: ML
authors.lastname: Athayde
authors.forename: Maribel A
authors.initials: MA
authors.lastname: Rubin
authors.forename: João B
authors.initials: JB
authors.lastname: Calixto
authors.forename: Juliano
authors.initials: J
authors.lastname: Ferreira
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists; D000700:Analgesics / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001572:Benzofurans; D004224:Diterpenes; D004333:Drug Administration Routes; D004353:Drug Evaluation, Preclinical; D019329:Idazoxan; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010147:Pain Measurement; D011720:Pyrazoles / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011759:Pyrrolidines; D011869:Radioligand Assay; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000037:antagonists & inhibitors; D050916:TRPV Cation Channels / Q000187:drug effects; D014316:Tritium
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D000700:Analgesics; D001572:Benzofurans; D004224:Diterpenes; D009292:Narcotic Antagonists; D011720:Pyrazoles; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D014316:Tritium; D009270:Naloxone; C051844:norbinaltorphimine; D009271:Naltrexone; C024353:resiniferatoxin; C067110:enadoline; D019329:Idazoxan
keywords: 5-hydroxy-3-methyl-5-(trichloromethyl)-1H-pyrazole-1-carboxamide; Antinociception; CLogP; Capsaicin; DMPE; MPCA; MPCIE; MPF4; MPFE; Methyl 3-methyl-5-(trifluoromethyl)-1H-pyrazole-1-carboxylate; Pyrazole; Sedation; [(3)H]-(5R)-(5a,7a,8b)-(−)-N-methyl-N-(7-[1-pyrrolidinyl]-1-oxaspiro[4,5]dec-8-yl)-4-benzofuranacetamide hydrochloride; [(3)H]-CI-977; [(3)H]-IDZ; [(3)H]-RTX; [(3)H]-idazoxan; [(3)H]-resiniferatoxin; coefficient of partition octanol/water; methyl 3,5-dimethyl-1H-pyrazole-1-carboxylate; methyl 3-methyl-5-(trichloromethyl)-1H-pyrazole-1-carboxylate; methyl 5-hydroxy-4-methyl-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazole-1-carboxylate; nor-BNI; nor-binaltorphimine; κ-Opioid receptor