title: Structural improvement of compounds with analgesic activity: AC-MPF4, a compound with mixed anti-inflammatory and antinociceptive activity via opioid receptor.
abstract: Successful pain control is a world health problem, which indicates an ever-growing need in the discovery of new molecules with improved analgesic activity and reduced side effects. The aim of this study was to describe the synthesis and biological activity of AC-MPF4, a new acetyl- and pyrazole-containing molecule derivate from MPF4. Firstly, we evaluated the analgesic and anti-edematogenic effect of AC-MPF4 in the carrageenan test. AC-MPF4 presented similar analgesic properties to MPF4 (opioid drug) and acetylsalicylic acid (ASA-a non-steroidal anti-inflammatory drug) (maximal effect of 85.4±10.9%, 62.0±11.0% and 95.0±10.4% of allodynia reduction, respectively). Regarding anti-edematogenic properties, AC-MPF4 presented similar results to ASA, while MPF4 presented no effect (maximal effect of 42.2±8.3% and 46.1±5.1% in paw thickness reduction, respectively). Remarkably, Naloxone fully prevented the analgesic effect of MPF4 and partially prevented the analgesic effect of AC-MPF4. However, neither ASA nor the anti-edematogenic activity was affected by Naloxone. The gastrointestinal motility and gastric mucosa integrity, which are parameters affected by opioid and NSAID drugs, respectively, were also evaluated. Neither of these parameters showed alterations induced by AC-MPF4, whereas ASA induced gastric ulceration (10 fold higher), and MPF4 decreased gastrointestinal motility (62.0±7.7%). Together, these data indicate that AC-MPF4 presents good analgesic and anti-edematogenic effects with no detectable side effects. AC-MPF4 may be considered a good prototype for the development of new analgesic/anti-inflammatory drugs.
authors.affiliation: Programa de Pós-Graduação em Ciências Biológicas, Bioquímica Toxicológica, Laboratório de Psicofarmacologia e Neurotoxicidade, Universidade Federal de Santa Maria, Brazil. Electronic address: mateus.rossato@gmail.com.
authors.forename: Mateus Fortes
authors.initials: MF
authors.lastname: Rossato
authors.affiliation: Programa de Pós-Graduação em Ciências Biológicas, Bioquímica Toxicológica, Laboratório de Psicofarmacologia e Neurotoxicidade, Universidade Federal de Santa Maria, Brazil.
authors.forename: Sara Marchesan
authors.initials: SM
authors.lastname: Oliveira
authors.affiliation: Programa de Pós-Graduação em Ciências Biológicas, Bioquímica Toxicológica, Laboratório de Psicofarmacologia e Neurotoxicidade, Universidade Federal de Santa Maria, Brazil.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Trevisan
authors.affiliation: Núcleo de Química de Heterociclos (NUQUIMHE), Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Brazil.
authors.forename: Mariane
authors.initials: M
authors.lastname: Rotta
authors.affiliation: Núcleo de Química de Heterociclos (NUQUIMHE), Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Brazil.
authors.forename: Pablo
authors.initials: P
authors.lastname: Machado
authors.affiliation: Núcleo de Química de Heterociclos (NUQUIMHE), Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Brazil.
authors.forename: Marcos A P
authors.initials: MA
authors.lastname: Martins
authors.affiliation: Programa de Pós-Graduação em Ciências Biológicas, Bioquímica Toxicológica, Laboratório de Psicofarmacologia e Neurotoxicidade, Universidade Federal de Santa Maria, Brazil.
authors.forename: Juliano
authors.initials: J
authors.lastname: Ferreira
mesh_terms: D000085:Acetates / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D000700:Analgesics / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D005769:Gastrointestinal Motility / Q000187:drug effects; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D011720:Pyrazoles / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000187:drug effects*; D013276:Stomach Ulcer / Q000139:chemically induced; D013329:Structure-Activity Relationship
chemical_list: D000085:Acetates; D000700:Analgesics; D000893:Anti-Inflammatory Agents; D011720:Pyrazoles; D011957:Receptors, Opioid; C000601925:methyl 5-acetoxy-4-methyl-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazole-1-carboxylate
keywords: Anti-inflammatory; Antinociception; Carrageenan; NSAID; Opioid; Pyrazole