Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 4 de 4
Filter
Add more filters










Database
Language
Publication year range
1.
Eur J Pharmacol ; 616(1-3): 91-100, 2009 Aug 15.
Article in English | MEDLINE | ID: mdl-19540223

ABSTRACT

Nonsteroidal antiinflammatory drugs (NSAIDs) are commonly used for treatment of arthritis. However, their long-term use has been associated with considerable morbidity, limiting their application. Thus, there remains a need to develop new drugs for the effective and safe relief of chronic inflammatory pain. In this context, the present study was designed to evaluate the antinociceptive and antiedematogenic effects of the 5-trifluoromethyl-4,5-dihydro-1H-pyrazole derivatives EPFCA3 and MPFCA4 after acute (1-1000 micromol/kg) and chronic (100 micromol/kg for 15 days) administration in rats submitted to a model of adjuvant-induced arthritis. We also analyzed some biochemical indicators of toxicity (alanine aminotransferase, aspartate aminotransferase, urea and creatinine levels) after prolonged administration of these compounds. We found that acute and chronic subcutaneuous administration of EPFCA3 and MPFCA4 produces an antinociceptive, but not antiedematogenic, effect on the arthritis animal model induced by complete Freund's adjuvant (CFA). No signs of toxicity were observed in the animals chronically treated with EPFCA3 or MPFCA4. Dipyrone (1-1000 micromol/kg) was used as the positive control and its effect was similar to that of the novel pyrazoles. The activity of tissue myeloperoxidase, the tissue TNF-alpha level and the serum haptoglobin level was increased by intraplantar CFA injection. However, chronic administration of EPFCA3, MPFCA4 or dipyrone was not able to alter the relation between these parameters and inflammation. Our results suggest that EPFCA3 and MPFCA4 are good candidates for the development of new drugs for pain treatment.


Subject(s)
Analgesics/pharmacology , Anti-Inflammatory Agents/pharmacology , Pain/drug therapy , Pyrazoles/pharmacology , Analgesics/administration & dosage , Analgesics/chemistry , Analgesics/therapeutic use , Animals , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/therapeutic use , Arthritis, Experimental/drug therapy , Arthritis, Experimental/enzymology , Arthritis, Experimental/metabolism , Arthritis, Experimental/pathology , Body Weight/drug effects , Chronic Disease/drug therapy , Creatinine/blood , Dipyrone/administration & dosage , Dipyrone/pharmacology , Disease Models, Animal , Dose-Response Relationship, Drug , Edema/blood , Edema/drug therapy , Edema/enzymology , Edema/pathology , Haptoglobins/metabolism , Inflammation/blood , Inflammation/drug therapy , Inflammation/enzymology , Inflammation/pathology , Leukocytes/drug effects , Leukocytes/metabolism , Male , Organ Size/drug effects , Pain/blood , Pain/enzymology , Pain/pathology , Pyrazoles/administration & dosage , Pyrazoles/chemistry , Pyrazoles/therapeutic use , Rats , Rats, Wistar , Reference Standards , Stomach/drug effects , Stomach/pathology , Time Factors , Tumor Necrosis Factor-alpha/metabolism , Urea/blood
2.
Bioorg Med Chem Lett ; 19(2): 546-9, 2009 Jan 15.
Article in English | MEDLINE | ID: mdl-19064321

ABSTRACT

A series of sixteen 2-substituted-2-imidazolines (where the substituent R=Ph, Me-4-Ph; MeO-4-Ph; (MeO)(2)-3,4-Ph; (MeO)(3)-3,4,5-Ph; Ph-4-O-C(O)-Ph; Cl-4-Ph; Cl-2-Ph; Cl(2)-2,4-Ph; NO(2)-4-Ph; NO(2)-3-Ph; Naphth-2-yl; Fur-2-yl; Benzofur-2-yl; Pyridin-2-yl; Quinolin-2-yl) has been synthesized from the reaction of the substituted-aldehydes and ethylenediamine by ultrasound irradiation with NBS in an aqueous medium in high yields (80-99%). The 2-imidazoline ability to inhibit the activity of the A and B isoforms of monoamine oxidase (MAO) was investigated and some of them showed potent and selective MAO inhibitory activity especially for the MAO-B isoform and could become promising candidates for future development.


Subject(s)
Imidazolines/chemical synthesis , Monoamine Oxidase Inhibitors/chemical synthesis , Imidazolines/pharmacology , Monoamine Oxidase Inhibitors/pharmacology , Ultrasonics , Water/chemistry
3.
Eur J Pharmacol ; 581(1-2): 86-96, 2008 Feb 26.
Article in English | MEDLINE | ID: mdl-18190906

ABSTRACT

The aim of the present study was to evaluate the antinociceptive potential of four novel pyrazoline methyl ester compounds on chemical and thermal models of pain in mice. The following 5-trihalomethylated-4,5-dihydro-1H-pyrazole methyl ester compounds were tested: 3-methyl-5-trifluoromethyl-(MPF3), 4-methyl-5-trifluoromethyl-(MPF4), 3-methyl-5-trichloromethyl-(MPCl3) and 4-methyl-5-trichloromethyl-(MPCl4). MPF3, MPF4, MPCl3 and MPCl4 (0.03-1.0 mmol/kg) given intraperitoneally decreased neurogenic and inflammatory phases of nociception in the formalin test. Moreover, MPF3, MPF4, MPCl3, MPCl4 (0.1-1.0 mmol/kg) and dipyrone (1.5 mmol/kg) also produced a dose-dependent antinociceptive effect in the hot-plate test. However, MPF3, MPF4, MPCl3 and MPCl4 did not impair motor coordination in the rotarod test or spontaneous locomotion in the open field test. The antinociceptive effect of MPF4 (1.0 mmol/kg, i.p.) was reversed by the opioid receptor antagonist naloxone (2 mg/kg, i.p.), but not by the alpha(2)-adrenergic receptor antagonist yohimbine (0.15 mg/kg, i.p.) or by p-chlorophenylalanine ethyl ester (PCPA, 300 mg/kg, i.p.) treatment. In contrast to morphine (5 mg/kg, i.p.), MPF4 given daily for up to 8 days did not generate a tolerance to its antinociceptive effect. However, similar to morphine (11 mg/kg, i.p.), MPF4 reduced gastrointestinal transit in mice. Taken together these results demonstrate that these novel pyrazoline methyl esters tested may be promising prototypes of additional mild analgesics.


Subject(s)
Analgesics/pharmacology , Pain Measurement/methods , Pyrazoles/pharmacology , Animals , Dose-Response Relationship, Drug , Drug Tolerance , Gastrointestinal Transit/drug effects , Male , Mice , Motor Activity/drug effects , Structure-Activity Relationship
4.
Eur J Med Chem ; 43(6): 1237-47, 2008 Jun.
Article in English | MEDLINE | ID: mdl-17889969

ABSTRACT

In this work, we reported the synthesis and evaluation of the analgesic and anti-inflammatory properties of novel 3- or 4-substituted 5-trifluoromethyl-5-hydroxy-4,5-dihydro-1H-1-carboxyamidepyrazoles (where 3-/4-substituent=H/H, Me/H, Et/H, Pr/H, i-Pr/H, Bu/H, t-Bu/H, Ph/H, 4-Br-Ph/H and H/Me) designed in the exploration of the bioisosteric replacement of benzene present in salicylamide with a 5-trifluoromethyl-4,5-dihydro-1H-pyrazole scaffold. Target compounds were synthesized from the cyclocondensation of 4-alkoxy-1,1,1-trifluoromethyl-3-alken-2-ones with semicarbazide hydrochloride through a rapid one-pot reaction via microwave irradiation. In addition to spectroscopic data, the structure of the compounds was supported by X-ray diffraction. Subcutaneous administration of the 5-trifluoromethyl-4,5-dihydro-1H-pyrazoles decreased pain-related behavior during neurogenic and inflammatory phases of the formalin test in mice. Moreover, the more active analgesic compounds (3-/4-=Et/H and H/Me) significantly decreased carrageenan-induced paw edema in mice. The data obtained in this work suggest that the synthesized compounds could be promising candidates for the future development of novel analgesic and anti-inflammatory agents.


Subject(s)
Analgesics/chemical synthesis , Analgesics/pharmacology , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacology , Drug Design , Microwaves , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Analgesics/chemistry , Animals , Anti-Inflammatory Agents/chemistry , Magnetic Resonance Spectroscopy , Male , Mice , Models, Molecular , Pyrazoles/chemistry , X-Ray Diffraction
SELECTION OF CITATIONS
SEARCH DETAIL
...