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1.
Bioorg Med Chem Lett ; 20(15): 4573-7, 2010 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-20584609

RESUMO

A new series of 2,3-diarylpyrroles have been prepared and evaluated as CB(1) antagonists. Modulation of the topological polar surface area allowed the identification of high affinity peripherally-restricted CB(1) antagonists. Compound 11, obtained after further optimization of the metabolic profile displayed very low brain penetration, yet was able to reverse CP55940-induced gastrointestinal transit inhibition following oral administration.


Assuntos
Piperidinas/química , Pirazóis/química , Pirróis/química , Administração Oral , Animais , Encéfalo/metabolismo , Desenho de Fármacos , Trânsito Gastrointestinal/efeitos dos fármacos , Piperidinas/síntese química , Piperidinas/farmacologia , Pirazóis/síntese química , Pirazóis/farmacologia , Pirróis/síntese química , Pirróis/farmacologia , Ratos , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/metabolismo , Rimonabanto
2.
Eur J Pharmacol ; 573(1-3): 206-13, 2007 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-17643417

RESUMO

Cannabinoids have been shown to inhibit sensory nerve activation in guinea-pigs and humans. Their effects are mediated by specific activation of two types of receptors, named CB(1) and CB(2). The purpose of this study was to investigate the effects of WIN 55,212-2, (R)-(+)-[2,3-dihydro-5methyl-3-[(4-morpholino)methyl]pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthyl)methanone, a non selective agonist of cannabinoid receptors, and JWH 133, (6aR,10aR)-3-(1,1-dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran a selective cannabinoid CB(2) receptor agonist, on the sensory nerve component of intraoesophageal (i.oe.) HCl-induced airway microvascular leakage and bronchoconstriction in guinea-pigs. We also tested the effect of WIN 55,212-2 on substance P-induced plasma extravasation and bronchoconstriction. Airway microvascular leakage and bronchoconstriction induced by i.oe. HCl was inhibited by the cannabinoid CB(1)/CB(2) agonist WIN 55,212-2 (0.3-3 mg/kg i.p.) in a dose-dependent manner (maximal inhibition at the dose of 3 mg kg(-1), P<0.01). The effect of WIN 55,212-2 was inhibited by a cannabinoid CB(2) receptor antagonist SR 144528, [N-[(1S)-endo-1,3,3-trimethylbicyclo[2,2,1] heptan-2yl]-5-(-4-chloro-3-methylphenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide], but not by a CB(1) receptor antagonist, SR 141716, [N-(piperidin-1yl)-5-(-4-chlorophenyl)-1-(2,4dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride]. The cannabinoid CB(2) agonist JWH 133 (0.3-3 mg/kg i.p.) mimicked the inhibitory effect of WIN 55,212-2 on HCl-induced microvascular leakage. Under similar conditions, WIN 55,212-2 (1 mg kg (-1) i.p.) was unable to counteract the airway microvascular leakage and bronchoconstriction induced by substance P. These results suggest that inhibition by WIN 55,212-2 of airway plasma extravasation and bronchoconstriction induced by i.oe. HCl instillation in guinea-pigs is mediated through cannabinoid CB(2) receptor activation.


Assuntos
Broncoconstrição/efeitos dos fármacos , Refluxo Gastroesofágico/prevenção & controle , Edema Pulmonar/prevenção & controle , Receptor CB2 de Canabinoide/agonistas , Obstrução das Vias Respiratórias/fisiopatologia , Obstrução das Vias Respiratórias/prevenção & controle , Animais , Benzoxazinas/farmacologia , Brônquios/irrigação sanguínea , Brônquios/efeitos dos fármacos , Brônquios/fisiopatologia , Broncoconstrição/fisiologia , Canfanos/farmacologia , Canabinoides/farmacologia , Permeabilidade Capilar/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Esôfago/efeitos dos fármacos , Extravasamento de Materiais Terapêuticos e Diagnósticos , Refluxo Gastroesofágico/fisiopatologia , Cobaias , Ácido Clorídrico/administração & dosagem , Ácido Clorídrico/toxicidade , Masculino , Morfolinas/farmacologia , Naftalenos/farmacologia , Piperidinas/farmacologia , Edema Pulmonar/fisiopatologia , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/fisiologia , Testes de Função Respiratória/métodos , Rimonabanto , Traqueia/irrigação sanguínea , Traqueia/efeitos dos fármacos , Traqueia/fisiopatologia
3.
Bull Acad Natl Med ; 191(4-5): 933-8; discussion 938-40, 2007.
Artigo em Francês | MEDLINE | ID: mdl-18225447

RESUMO

The endocannabinoid (EC) system is a physiological system with an important regulatory role in numerous biological functions, both centrally and peripherally. In certain conditions it can become hyperactive and induce a variety of disorders. The system has two receptor types, designated CB1 and CB2 (present respectively in the CNS and the periphery), as well as endogenous ligands (AEA and 2-AG) and equipment for transporting, synthesizing and degrading them. The discovery of specific CB1 antagonists has opened up interesting new possibilities for the treatment of obesity, diabetes and cardiometabolic risk factors.


Assuntos
Antagonistas de Receptores de Canabinoides , Canabinoides/antagonistas & inibidores , Diabetes Mellitus Tipo 2/tratamento farmacológico , Obesidade/tratamento farmacológico , Piperidinas/uso terapêutico , Pirazóis/uso terapêutico , Animais , Regulação do Apetite/efeitos dos fármacos , Moduladores de Receptores de Canabinoides/uso terapêutico , Canabinoides/farmacologia , Ensaios Clínicos Fase III como Assunto , Diabetes Mellitus Tipo 2/sangue , Modelos Animais de Doenças , Dislipidemias/tratamento farmacológico , Humanos , Ligantes , Camundongos , Camundongos Knockout , Piperidinas/administração & dosagem , Piperidinas/farmacologia , Pirazóis/administração & dosagem , Pirazóis/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Ratos , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/efeitos dos fármacos , Receptor CB2 de Canabinoide/fisiologia , Receptores de Canabinoides/efeitos dos fármacos , Receptores de Canabinoides/fisiologia , Rimonabanto , Fatores de Risco
4.
Life Sci ; 77(13): 1425-40, 2005 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-15894337

RESUMO

The pharmacological and neuroprotective properties of two ester analogs of the endocannabinoids, arachidonoylethyleneglycol (AA-EG) and alpha,alpha,-dimethyl arachidonoylethyleneglycol (DMA-EG), were investigated. We examined the interaction of both compounds with cannabinoid receptors (CB1 and CB2) and their efficacy in functional assays. In competition binding assays, AA-EG and DMA-EG had low potency to displace the CB1/CB2 agonist [3H]CP-55,940 in membrane preparations expressing rodent or human receptors. Binding data correlate with low efficacy of both compounds as regards to inhibition of adenylyl cyclase activity. It was also shown that DMA-EG resists hydrolysis by rat brain membranes while AA-EG undergo complete splitting under these conditions. In the cannabinoid tetrad, AA-EG induced hypomotility, analgesia, catalepsy and decreased rectal temperature indicating cannabimimetic activity. By contrast, DMA-EG was completely inactive in the same models. DMA-EG and AA-EG potently protected rat cortical neurons in culture against oxygen deprivation at nanomolar concentrations. In glutamate-induced damage, the compounds were less active protecting neurons at micromolar concentrations. The data obtained indicate that the ester endocannabinoid template can be used for the development of new compounds with potent biological activity lacking some of the undesirable behavioral side effects.


Assuntos
Ácidos Araquidônicos/farmacologia , Moduladores de Receptores de Canabinoides/farmacologia , Endocanabinoides , Etilenoglicóis/farmacologia , Fármacos Neuroprotetores/farmacologia , Animais , Ligação Competitiva , Células CHO , Células Cultivadas , Cricetinae , AMP Cíclico/metabolismo , Cicloexanóis/metabolismo , Feminino , Ratos , Ratos Sprague-Dawley , Receptor CB2 de Canabinoide/metabolismo
5.
J Pharmacol Exp Ther ; 310(3): 905-14, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15131245

RESUMO

Based on binding, functional, and pharmacological data, this study introduces SR147778 [5-(4-bromophenyl)-1-(2,4-dichloro-phenyl)-4-ethyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide] as a highly potent, selective, and orally active antagonist for the CB1 receptor. This compound displays nanomolar affinity (Ki = 0.56 and 3.5 nM) for both the rat brain and human CB1 recombinant receptors, respectively. It has low affinity (Ki = 400 nM) for both the rat spleen and human CB2 receptors. Furthermore, it shows no affinity for any of the over 100 targets investigated (IC50 > 1 microM). In vitro, SR147778 antagonizes the inhibitory effects of CP 55,940 [(1R,3R,4R)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol] on both the mouse vas deferens contractions (pA2 value = 8.1) and on forskolin-stimulated adenylyl cyclase activity in the U373 MG cell lines (pA2 value = 8.2) but not in Chinese hamster ovary (CHO) cells permanently expressing the human peripheral cannabinoid receptor (hCB2). SR147778 is able to block the mitogen-activated protein kinase activity induced by CP 55,940 in the CHO cell line expressing human brain cannabinoid receptor (IC50 = 9.6 nM) but was inactive in cells expressing hCB2. After oral administration, SR147778 displaced the ex vivo [3H]-CP 55,940 binding to mouse brain membranes (ED50 = 3.8 mg/kg) with a long duration of action, whereas it did not interact with the CB2 receptor expressed in the mouse spleen. Using different routes of administration, SR147778 (0.3-3 mg/kg) is shown to antagonize pharmacological effects (hypothermia, analgesia, and gastrointestinal transit) induced by R-(+)-(2,3-dihydro-5-methyl-3-[[4-morpholinyl]methyl] pyrol [1,2,3-de]-1,4-benzoxazin-6-yl)(1-naphthalenyl) methanone in mice. Finally, per se, SR147778 (0.3-10 mg/kg) is able to reduce ethanol or sucrose consumption in mice and rats and food intake in fasted and nondeprived rats.


Assuntos
Piperidinas/farmacologia , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Animais , Ligação Competitiva , Células CHO , Cricetinae , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Especificidade da Espécie
6.
Nucl Med Biol ; 29(6): 671-7, 2002 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12234592

RESUMO

Two radioligands, [(11)C] SR149080 and its morpholino analog [(11)C] SR149568, were synthesized by reaction of the respective phenolic precursors with [(11)C] methyl iodide. Both radioligands had appropriate regional brain distribution for cannabinoid receptors in mice with peak target to non-target ratios of 2.2 for [(11)C] SR149080 and 1.6 for [(11)C] SR149568 at 90 and 30 minutes post-injection respectively. The uptake of both tracers was blocked with a 1 mg/kg dose of SR141716A.


Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Radioisótopos de Carbono/farmacocinética , Morfolinas/farmacocinética , Piperidinas/farmacocinética , Pirazóis/farmacocinética , Receptores de Droga/metabolismo , Animais , Masculino , Camundongos , Morfolinas/síntese química , Piperidinas/síntese química , Pirazóis/síntese química , Cintilografia , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Receptores de Canabinoides , Sensibilidade e Especificidade
7.
Eur J Pharmacol ; 450(1): 77-83, 2002 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-12176112

RESUMO

We studied the delay in gastric emptying and gastrointestinal transit induced by the cannabinoid receptor agonists (+)-WIN 55,212-2 (R(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl)methanone mesylate) and CP 55,940 ((-)-cis-3[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol), as prevented by the selective cannabinoid CB(1)-receptor antagonist SR141716 ((N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide)) in rats after systemic or central drug administration. Oral SR141716 showed comparable potency (ID(50) range 1.0-3.9 mg/kg) in antagonizing gastric emptying and gastrointestinal transit delay by (+)-WIN 55,212-2 or CP 55,940. Gastric emptying and gastrointestinal transit delay after intracerebroventricular (i.c.v.) (+)-WIN 55,212-2 was prevented by oral or i.c.v. SR141716, but i.c.v. SR141716 did not significantly reduce the effect of i.p. (+)-WIN 55,212-2. Pertussis toxin prevented the delaying action of i.c.v. (+)-WIN 55,212-2 on both gastric emptying and gastrointestinal transit, but had no effect on (+)-WIN 55,212-2 i.p. These findings are consistent with a primary role of peripheral cannabinoid CB(1) receptor mechanisms in gastrointestinal transit delay by specific agonists.


Assuntos
Canabinoides/metabolismo , Cicloexanóis/farmacologia , Esvaziamento Gástrico/efeitos dos fármacos , Trânsito Gastrointestinal/efeitos dos fármacos , Morfolinas/farmacologia , Naftalenos/farmacologia , Receptores de Droga/antagonistas & inibidores , Administração Oral , Análise de Variância , Animais , Benzoxazinas , Cicloexanóis/administração & dosagem , Relação Dose-Resposta a Droga , Injeções Intraventriculares , Masculino , Morfolinas/administração & dosagem , Naftalenos/administração & dosagem , Piperidinas/farmacologia , Pirazóis/farmacologia , Ratos , Receptores de Canabinoides , Receptores de Droga/fisiologia , Rimonabanto
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