4-nerolidylcatechol and Pleurisy

We have investigated the anti-inflammatory and antinociceptive effects of (E)-4-(3,7-dimethylocta-2,6-dienylamino)phenol (LQFM-015), which was designed through molecular simplification strategy from 4-nerolidylcatechol.. The possible anti-inflammatory and antinociceptive effects were assayed on carrageenan-induced paw oedema and pleurisy, acetic acid-induced abdominal writhing and formalin tests in mice..  LQFM-015 reduced the activity of PLA₂ enzyme in vitro by 18%. Docking studies into the catalytic site of PLA₂ were used to identify the binding mode of the LQFM-015. LQFM-015 showed a moderate antinociceptive effect, since this compound reduced the number of writhings by approximately up to 40% in the acetic acid-induced pain model; this antinociceptive activity also emerged in the second phase of the formalin-induced pain model (58% of inhibition). The anti-inflammatory action of LQFM-015 was confirmed in acute inflammation models, in which it reduced the formation of oedema to 52.78 ± 8.6 and 46.64 ± 5.2 at the second and third hour of carrageenan-induced paw oedema, respectively. Also in the carrageenan-induced pleurisy model, LQFM-015 reduced the migration of leucocytes by 26.0% and decrease myeloperoxidase activity by 50%. LQFM-015 showed different concentrations to inhibit 50% of isoenzyme cyclooxygenase activity (IC50); COX-1 IC50 = 36 μM) and COX-2 IC50 = 28 μM.. LQFM-015 demonstrated inhibition of both PLA₂ and COX enzymes; thus, the moderate antinociceptive effect of this compound could be attributed to its anti-inflammatory activity.

Topics: Abdominal Pain; Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Catalytic Domain; Catechols; Cell Movement; Dose-Response Relationship, Drug; Drug Design; Edema; Enzyme Inhibitors; Lymphocytes; Male; Mice; Molecular Conformation; Molecular Docking Simulation; Oxidoreductases; Phospholipase A2 Inhibitors; Phospholipases A2; Pleurisy; Stereoisomerism

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.. 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.. 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 (3mg/kg) reversed the analgesic effects of LQFM002 in the early phase of the formalin test.. 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.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Capillary Permeability; Carrageenan; Catechols; Cell Movement; Drug Evaluation, Preclinical; Leukocytes; Male; Mice; Phospholipase A2 Inhibitors; Phospholipases A2; Pleurisy; Pyrazoles; Tumor Necrosis Factor-alpha