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1.
J Med Chem ; 63(5): 2372-2390, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-31790581

RESUMO

Neuropathic pain (NP) is a complex chronic pain state with a prevalence of almost 10% in the general population. Pharmacological options for NP are limited and weakly effective, so there is a need to develop more efficacious NP attenuating drugs. Activation of the type 1 lysophosphatidic acid (LPA1) receptor is a crucial factor in the initiation of NP. Hence, it is conceivable that a functional antagonism strategy could lead to NP mitigation. Here we describe a new series of LPA1 agonists among which derivative (S)-17 (UCM-05194) stands out as the most potent and selective LPA1 receptor agonist described so far (Emax = 118%, EC50 = 0.24 µM, KD = 19.6 nM; inactive at autotaxin and LPA2-6 receptors). This compound induces characteristic LPA1-mediated cellular effects and prompts the internalization of the receptor leading to its functional inactivation in primary sensory neurons and to an efficacious attenuation of the pain perception in an in vivo model of NP.


Assuntos
Analgésicos/química , Analgésicos/uso terapêutico , Neuralgia/tratamento farmacológico , Receptores de Ácidos Lisofosfatídicos/agonistas , Animais , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Descoberta de Drogas , Feminino , Humanos , Hidrocarbonetos Aromáticos/química , Hidrocarbonetos Aromáticos/uso terapêutico , Camundongos Endogâmicos C57BL , Modelos Moleculares , Neuralgia/metabolismo , Percepção da Dor/efeitos dos fármacos , Ratos Wistar , Receptores de Ácidos Lisofosfatídicos/metabolismo , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismo
2.
Sci Rep ; 7(1): 2020, 2017 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-28515494

RESUMO

Sphingosine-1-phosphate (S1P) is a lipid mediator that can activate five cell membrane G protein-coupled receptors (GPCRs) which carry a variety of essential functions and are promising drug targets. S1P is composed of a polar zwitterionic head-group and a hydrophobic alkyl chain. This implies an activation mechanism of its cognate receptor that must be significantly different from what is known for prototypical GPCRs (ie receptor to small hydrophilic ligands). Here we aim to identify the structural features responsible for S1P agonism by combining molecular dynamics simulations and functional assays using S1P analogs of different alkyl chain lengths. We propose that high affinity binding involves polar interactions between the lipid head-group and receptor side chains while activation is due to hydrophobic interactions between the lipid tail and residues in a distinct binding site. We observe that ligand efficacy is directly related to alkyl chain length but also varies with receptor subtypes in correlation with the size of this binding pocket. Integrating experimental and computational data, we propose an activation mechanism for the S1P receptors involving agonist-induced conformational events that are conserved throughout class A GPCRs.


Assuntos
Lipídeos/química , Receptores Acoplados a Proteínas G/química , Animais , Sítios de Ligação , Células CHO , Cricetulus , Ligantes , Metabolismo dos Lipídeos , Lisofosfolipídeos/química , Lisofosfolipídeos/metabolismo , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Ligação Proteica , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Lisoesfingolipídeo/química , Receptores de Lisoesfingolipídeo/metabolismo , Esfingosina/análogos & derivados , Esfingosina/química , Esfingosina/metabolismo , Relação Estrutura-Atividade
3.
PLoS One ; 7(11): e49057, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23152849

RESUMO

Spinal cord injury (SCI) induces a cascade of processes that may further expand the damage (secondary injury) or, alternatively, may be part of a safeguard response. Here we show that after a moderate-severe contusive SCI in rats there is a significant and very early increase in the spinal cord content of the endocannabinoids 2-arachidonoylglycerol (2-AG) and arachidonoyl ethanolamide (anandamide, AEA). Since 2-AG and AEA act through CB1 and CB2 cannabinoid receptors, we administered at 20 minutes after lesion a single injection of their respective antagonists AM281 and AM630 alone or in combination to block the effects of this early endocannabinoid accumulation. We observed that AM281, AM630 or AM281 plus AM630 administration impairs the spontaneous motor recovery of rats according to the Basso-Beattie-Bresnahan (BBB) locomotor scale. However, blockade of CB1, CB2 or both receptors produced different effects at the histopathological level. Thus, AM630 administration results at 90 days after lesion in increased MHC-II expression by spinal cord microglia/monocytes and reduced number of serotoninergic fibres in lumbar spinal cord (below the lesion). AM281 exerted the same effects but also increased oedema volume estimated by MRI. Co-administration of AM281 and AM630 produced the effects observed with the administration of either AM281 or AM630 and also reduced white matter and myelin preservation and enhanced microgliosis in the epicentre. Overall, our results suggest that the endocannabinoids acting through CB1 and CB2 receptors are part of an early neuroprotective response triggered after SCI that is involved in the spontaneous recovery after an incomplete lesion.


Assuntos
Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Recuperação de Função Fisiológica , Traumatismos da Medula Espinal/prevenção & controle , Traumatismos da Medula Espinal/fisiopatologia , Animais , Endocanabinoides/metabolismo , Gliose/complicações , Gliose/patologia , Gliose/fisiopatologia , Locomoção , Vértebras Lombares/patologia , Vértebras Lombares/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Microglia/metabolismo , Microglia/patologia , Atividade Motora/efeitos dos fármacos , Bainha de Mielina/metabolismo , Bainha de Mielina/patologia , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/antagonistas & inibidores , Neurônios Serotoninérgicos/metabolismo , Neurônios Serotoninérgicos/patologia , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Temperatura
4.
J Med Chem ; 55(2): 824-36, 2012 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-22185522

RESUMO

The two endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), play independent and nonredundant roles in the body. This makes the development of both selective and dual inhibitors of their inactivation an important priority. In this work we report a new series of inhibitors of monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH). Among them, (±)-oxiran-2-ylmethyl 6-(1,1'-biphenyl-4-yl)hexanoate (8) and (2R)-(-)-oxiran-2-ylmethyl(4-benzylphenyl)acetate (30) stand out as potent inhibitors of human recombinant MAGL (IC(50) (8) = 4.1 µM; IC(50) (30) = 2.4 µM), rat brain monoacylglycerol hydrolysis (IC(50) (8) = 1.8 µM; IC(50) (30) = 0.68 µM), and rat brain FAAH (IC(50) (8) = 5.1 µM; IC(50) (30) = 0.29 µM). Importantly, and in contrast to the other previously described MAGL inhibitors, these compounds behave as reversible inhibitors either of competitive (8) or noncompetitive nature (30). Hence, they could be useful to explore the therapeutic potential of reversible MAGL inhibitors.


Assuntos
Amidoidrolases/antagonistas & inibidores , Compostos de Bifenilo/síntese química , Compostos de Epóxi/síntese química , Monoacilglicerol Lipases/antagonistas & inibidores , Fenilacetatos/síntese química , Amidoidrolases/química , Animais , Compostos de Bifenilo/química , Compostos de Epóxi/química , Humanos , Cinética , Modelos Moleculares , Monoacilglicerol Lipases/química , Fenilacetatos/química , Ratos , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/química , Estereoisomerismo , Relação Estrutura-Atividade
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