Anti-inflammatory and antinociceptive activities of LQFM002 — A 4-nerolidylcatechol derivative E.A. Costa a, ⁎, R.C. Lino a , M.N. Gomes b , M.V.M. Nascimento a , I.F. Florentino a , P.M. Galdino a , C.H. Andrade c , K.R. Rezende d , L.O. Magalhães b , R. Menegatti b a Institute of Biological Sciences, Department of Physiological Sciences, Federal University of Goiás, Campus Samambaia, Caixa Postal 131, CEP 74001-970, Goiânia, GO, Brazil b Faculty of Pharmacy, Laboratory of Medicinal Pharmaceutical Chemistry, Federal University of Goiás, Goiânia, GO, Brazil c Faculty of Pharmacy, Laboratory of Molecular Modeling, Federal University of Goiás, Goiânia, GO, Brazil d Faculty of Pharmacy, Laboratory of Biopharmacy and Pharmacokinetic, Federal University of Goiás, Goiânia, GO, Brazil abstract article info Article history: Received 31 January 2012 Accepted 14 December 2012 Keywords: Antinociception Anti-inflammatory PLA 2 activity TNF-α Aims: The current study describes the synthesis and pharmacological evaluation of (E)-N-(3,7-dimethylocta- 2,6-dienyl)-1,3-dimethyl-1H-pyrazol-5-amine (LQFM002), a compound originally designed through a molecular simplification strategy from 4-nerolidylcatechol. LQFM002 was evaluated for preservation of the PLA 2 enzyme inhibitory effects of the lead compound, 4-nerolidylcatechol, using in vitro and in vivo models. Main methods: Rota-rod, open field and pentobarbital-induced sleeping tests were used to evaluate the effects of LQFM002 on the central nervous system. A gel plate assay of PLA 2 activity, carrageenan-induced pleurisy and TNF-α levels was used to assay anti-inflammatory activity. Antinociceptive activities of LQFM002 were evaluated with acetic acid-induced writhing, formalin and hot-plate tests, while involvement of the opioid pathway in the LQFM002 antinociceptive effect was investigated with naloxone pre-treatment. Key findings: LQFM002 inhibited PLA 2 activity, cell migration into the pleural cavity, and capillary permeability (Evan's blue concentration) and reduced TNF-α levels in pleural exudates. LQFM002 also reduced acetic acid-induced writhing and the licking time in both phases of the formalin test and increased latency in the hot-plate test. Pre-treatment with 8.25 μmol/kg naloxone (3 mg/kg) reversed the analgesic effects of LQFM002 in the early phase of the formalin test. Significance: LQFM002 showed anti-inflammatory activity, which possibly involved reduction of leukocyte migration and TNF-α levels. LQFM002 also demonstrated inhibition of PLA 2 activity in vitro. LQFM002 had an antinociceptive effect that involved the opioidergic system. © 2013 Elsevier Inc. All rights reserved. Introduction Inflammatory response is a complex process mediated by a variety of signaling molecules released by nerve endings, mast cells, platelets and leukocytes. Some of these molecules and their precursors (prostaglan- dins, nitric oxide, adenosine deaminase and myeloperoxidase) are used as markers of inflammation (Kalkan et al., 1999). Study of inflammation with carrageenan as a phlogistic agent has revealed increased vascular permeability, formation of exudate and a large number of cellular infil- trates as polymorphonuclear leukocytes (Hambleton and Miller, 1989). Tumor necrosis factor alpha (TNF-α), an important inflammatory mediator, is a multifunctional cytokine that can regulate many cellular and biological processes, such as immune function, cell differentiation, proliferation, apoptosis, and energy metabolism. Furthermore, TNF-α can regulate the production of other pro-inflammatory cytokines, such as interleukin-6 (IL-6) and interleukin-1 (IL-1), to mediate and/ or amplify their effects in peripheral organs (Cawthorn and Sethi, 2008). During the acute inflammatory process, overproduction of TNF-α is crucial to the induction of inflammatory genes and the recruit- ment and activation of host immune cells (Bhatia et al., 2005). Currently, several anti-inflammatory agents are used to treat differ- ent types of pain associated with inflammation. These agents are effi- cient in most cases, but side effects are common, especially when they are used chronically. The most common side effect is gastrointestinal disturbance (Peura and Goldkind, 2005). Many companies have investi- gated the synthesis and semisynthesis of lead compounds from medic- inal plants used in folk medicine for the development of new drugs (Newman et al., 2003). 4-Nerolidylcatechol (4-NC) is a compound isolated from Piper umbellatum, Piper peltatum and Pothomorphe peltata (Piperaceae) (Zamora-Martínez and De Pascual Pola, 1992; Akendengué and Louis, 1994; Desmarchelier et al., 2000). The methanolic extract from P. peltatum leaves shows anti-inflammatory effects in the Life Sciences 92 (2013) 237–244 ⁎ Corresponding author at: Laboratório de Farmacologia de Produtos Naturais, Sala 216, ICB-2 Universidade Federal de Goiás, CP 131, CEP 74001-970, Goiânia, GO, Brazil. Tel.: +55 62 3521 1491; fax: +55 62 352 11204. E-mail address: xico@icb.ufg.br (E.A. Costa). 0024-3205/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.lfs.2012.12.003 Contents lists available at SciVerse ScienceDirect Life Sciences journal homepage: www.elsevier.com/locate/lifescie