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1.
Microorganisms ; 9(1)2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33467609

RESUMO

A Staphylococcus aureus four-antigen vaccine (SA4Ag) was designed for the prevention of invasive disease in surgical patients. The vaccine is composed of capsular polysaccharide type 5 and type 8 CRM197 conjugates, a clumping factor A mutant (Y338A-ClfA) and manganese transporter subunit C (MntC). S. aureus pathogenicity is characterized by an ability to rapidly adapt to the host environment during infection, which can progress from a local infection to sepsis and invasion of distant organs. To test the protective capacity of the SA4Ag vaccine against progressive disease stages of an invasive S. aureus infection, a deep tissue infection mouse model, a bacteremia mouse model, a pyelonephritis model, and a rat model of infectious endocarditis were utilized. SA4Ag vaccination significantly reduced the bacterial burden in deep tissue infection, in bacteremia, and in the pyelonephritis model. Complete prevention of infection was demonstrated in a clinically relevant endocarditis model. Unfortunately, these positive preclinical findings with SA4Ag did not prove the clinical utility of SA4Ag in the prevention of surgery-associated invasive S. aureus infection.

2.
Nanoscale ; 12(7): 4418-4425, 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32026916

RESUMO

Plasmonic structure color has significant potential for visual biochemical sensing by simple instrumentation or even naked eye detection. Herein, we present a visual and real-time sensing strategy for refraction index sensing and detection of the biotin-avidin system based on three-dimensional cavity-coupled metamaterials. These metamaterials composed of a top array of gold disks, aluminium pillars and a bottom reflection film of aluminium have structures similar to the metal-insulator-metal structure. The insulating layer comprises air-gap cavities that are easily filled with gaseous or liquid dielectrics. Therefore, analytes can permeate into the nano-scale cavities and produce strong light-matter interactions. The sensor shows that any tiny change in the refraction index will induce a significant color variation and the sensitivity reaches 683.5 nm per refraction index unit with a figure of merit of 3.5. The color of the metamaterials changes from rose-red to violet and then loden after a monomolecular layer of thiolated biotin and streptavidin bind to the surface of the nanostructure successively. This sensing strategy offers new opportunities for the convenient detection of proteins, nucleic acids, and lipids.


Assuntos
Ouro/química , Nanopartículas Metálicas/química , Ressonância de Plasmônio de Superfície , Colorimetria , Lipídeos/análise , Ácidos Nucleicos/análise , Proteínas/análise
3.
Nanomaterials (Basel) ; 8(7)2018 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-30002295

RESUMO

Technology transfer from laboratory into practical application needs to meet the demands of economic viability and operational simplicity. This paper reports a simple and convenient strategy to fabricate large-scale and ultrasensitive surface-enhanced Raman scattering (SERS) substrates. In this strategy, no toxic chemicals or sophisticated instruments are required to fabricate the SERS substrates. On one hand, Ag nanoparticles (NPs) with relatively uniform size were synthesized using the modified Tollens method, which employs an ultra-low concentration of Ag⁺ and excessive amounts of glucose as a reducing agent. On the other hand, when a drop of the colloidal Ag NPs dries on a horizontal solid surface, the droplet becomes ropy, turns into a layered structure under gravity, and hardens. During evaporation, capillary flow was burdened by viscidity resistance from the ropy glucose solution. Thus, the coffee-ring effect is eliminated, leading to a uniform deposition of Ag NPs. With this method, flat Ag NPs-based SERS active films were formed in array-well plates defined by hole-shaped polydimethylsiloxane (PDMS) structures bonded on glass substrates, which were made for convenient detection. The strong SERS activity of these substrates allowed us to reach detection limits down to 10-14 M of Rhodamine 6 G and 10-10 M of thiram (pesticide).

4.
Mol Pharmacol ; 78(6): 996-1003, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20855465

RESUMO

Endocannabinoids are lipid molecules that serve as natural ligands for the cannabinoid receptors CB1 and CB2. They modulate a diverse set of physiological processes such as pain, cognition, appetite, and emotional states, and their levels and functions are tightly regulated by enzymatic biosynthesis and degradation. 2-Arachidonoylglycerol (2-AG) is the most abundant endocannabinoid in the brain and is believed to be hydrolyzed primarily by the serine hydrolase monoacylglycerol lipase (MAGL). Although 2-AG binds and activates cannabinoid receptors in vitro, when administered in vivo, it induces only transient cannabimimetic effects as a result of its rapid catabolism. Here we show using a mouse model with a targeted disruption of the MAGL gene that MAGL is the major modulator of 2-AG hydrolysis in vivo. Mice lacking MAGL exhibit dramatically reduced 2-AG hydrolase activity and highly elevated 2-AG levels in the nervous system. A lack of MAGL activity and subsequent long-term elevation of 2-AG levels lead to desensitization of brain CB1 receptors with a significant reduction of cannabimimetic effects of CB1 agonists. Also consistent with CB1 desensitization, MAGL-deficient mice do not show alterations in neuropathic and inflammatory pain sensitivity. These findings provide the first genetic in vivo evidence that MAGL is the major regulator of 2-AG levels and signaling and reveal a pivotal role for 2-AG in modulating CB1 receptor sensitization and endocannabinoid tone.


Assuntos
Moduladores de Receptores de Canabinoides/fisiologia , Endocanabinoides , Monoacilglicerol Lipases/metabolismo , Receptor CB1 de Canabinoide/fisiologia , Animais , Ativação Enzimática/genética , Ativação Enzimática/fisiologia , Hidrólise , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Monoacilglicerol Lipases/deficiência , Monoacilglicerol Lipases/fisiologia , Medição da Dor/métodos
5.
Neuropharmacology ; 59(3): 160-6, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20470804

RESUMO

Corticotropin-releasing factor (CRF) plays a major role in controlling the body's response to stress. Because painful conditions are inherently stressful, we hypothesize that CRF may act via CRF-1 receptors to contribute to the pain experience. Studies were designed to investigate whether blocking CRF-1 receptors with selective antagonists or reducing their expression with CRF-Saporin, would attenuate ulcer, inflammatory- and neuropathic-like pain. Five experimental designs were undertaken. In experiment 1, ulcer pain was induced in mice following oral administration of indomethacin, while in experiments 2 and 3, inflammatory pain was induced in rats with either carrageenan or FCA, respectively. For these studies, animals were dosed with CP-154,526 (3, 10, 30 mg/kg) and NBI 27914 (1-30 mg/kg) 1 h prior to the assessment of tactile, thermal or mechanical hypersensitivity, respectively. In experiment 4, neuropathic pain was induced. Twenty-one days following spinal nerve ligation (SNL), animals received CRF-Saporin or control. Three weeks later tactile allodynia was assessed. Similarly, in experiment 5, a separate set of rats received CRF-Saporin or control. Twenty-one days later, mechanical hyperalgesia was assessed following intraplantar carrageenan. Results from the antagonist studies showed that CP-154,526 and NBI 27914 either fully or partially reversed the referred ulcer pain with minimal effective doses (MED) equal to 3 and 10 mg/kg, respectively. Similarly, both NBI 27914 and CP-154,526 reversed the thermal and mechanical hypersensitivity elicited by carrageenan and FCA with MEDs

Assuntos
Dor/complicações , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Estresse Psicológico/etiologia , Estresse Psicológico/metabolismo , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Carragenina , Hormônio Liberador da Corticotropina/farmacologia , Hormônio Liberador da Corticotropina/uso terapêutico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Esquema de Medicação , Interações Medicamentosas , Hiperalgesia/tratamento farmacológico , Indometacina/farmacologia , Indometacina/uso terapêutico , Inflamação/induzido quimicamente , Inflamação/complicações , Masculino , Camundongos , Dor/tratamento farmacológico , Dor/etiologia , Limiar da Dor/efeitos dos fármacos , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Traumatismos da Medula Espinal/complicações , Úlcera Gástrica/complicações , Úlcera Gástrica/tratamento farmacológico , Estresse Psicológico/tratamento farmacológico
6.
J Neurosci ; 30(6): 2017-24, 2010 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-20147530

RESUMO

Endocannabinoids (eCBs) function as retrograde signaling molecules at synapses throughout the brain, regulate axonal growth and guidance during development, and drive adult neurogenesis. There remains a lack of genetic evidence as to the identity of the enzyme(s) responsible for the synthesis of eCBs in the brain. Diacylglycerol lipase-alpha (DAGLalpha) and -beta (DAGLbeta) synthesize 2-arachidonoyl-glycerol (2-AG), the most abundant eCB in the brain. However, their respective contribution to this and to eCB signaling has not been tested. In the present study, we show approximately 80% reductions in 2-AG levels in the brain and spinal cord in DAGLalpha(-/-) mice and a 50% reduction in the brain in DAGLbeta(-/-) mice. In contrast, DAGLbeta plays a more important role than DAGLalpha in regulating 2-AG levels in the liver, with a 90% reduction seen in DAGLbeta(-/-) mice. Levels of arachidonic acid decrease in parallel with 2-AG, suggesting that DAGL activity controls the steady-state levels of both lipids. In the hippocampus, the postsynaptic release of an eCB results in the transient suppression of GABA-mediated transmission at inhibitory synapses; we now show that this form of synaptic plasticity is completely lost in DAGLalpha(-/-) animals and relatively unaffected in DAGLbeta(-/-) animals. Finally, we show that the control of adult neurogenesis in the hippocampus and subventricular zone is compromised in the DAGLalpha(-/-) and/or DAGLbeta(-/-) mice. These findings provide the first evidence that DAGLalpha is the major biosynthetic enzyme for 2-AG in the nervous system and reveal an essential role for this enzyme in regulating retrograde synaptic plasticity and adult neurogenesis.


Assuntos
Encéfalo/metabolismo , Moduladores de Receptores de Canabinoides/fisiologia , Endocanabinoides , Lipase Lipoproteica/genética , Animais , Ácidos Araquidônicos/metabolismo , Encéfalo/citologia , Glicerídeos/metabolismo , Hipocampo/citologia , Hipocampo/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Knockout , Neurogênese , Plasticidade Neuronal , Transdução de Sinais , Medula Espinal/metabolismo , Sinapses/fisiologia
7.
Brain Res ; 1295: 89-98, 2009 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-19651113

RESUMO

Validation of gait analysis has the potential to bridge the gap between data from animal pain models and clinical observations. The goal of these studies was to compare alterations in gait due to inflammation or nerve injury to traditional pain measurements in animals. Pharmacological experiments determined whether gait alterations were related to enhanced nociception, edema, or motor nerve dysfunction. Gait was analyzed using an automated system (DigiGait) after injection of an inflammatory agent (carrageenan; CARR or FCA; Freund's complete adjuvant) or nerve injury (axotomy; AXO, partial sciatic nerve ligation; PSNL, spinal nerve ligation; SNL or chronic constriction injury; CCI). All models caused significant alterations in gait and thermal (inflammatory) or mechanical (nerve injury) hyperalgesia. Both indomethacin and morphine were able to block or reverse thermal hyperalgesia and normalize gait in the CARR model. Indomethacin partially blocked and did not reverse paw edema, suggesting that gait alterations must be primarily driven by enhanced nociception. In nerve injury models, AXO, PSNL, CCI, and SNL caused changes to the largest number of gait indices with the rank order being AXO>PSNL=CCI >> SNL. Gabapentin and duloxetine reversed mechanical hyperalgesia but did not normalize gait in any nerve injury model. Collectively, these data suggest that pain is the primary driver of abnormal gait in models of inflammatory but not nerve injury-related pain and suggests that, in the latter, disruption in gait is due to perturbation to the motor system. Gait may therefore constitute an alternative and potentially clinically relevant measure of pain due to inflammation.


Assuntos
Marcha/efeitos dos fármacos , Inflamação/fisiopatologia , Dor/fisiopatologia , Nervo Isquiático/lesões , Aminas/farmacologia , Analgésicos Opioides/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Axotomia , Carragenina , Ácidos Cicloexanocarboxílicos/farmacologia , Cloridrato de Duloxetina , Edema/induzido quimicamente , Edema/fisiopatologia , Adjuvante de Freund , Gabapentina , Marcha/fisiologia , Temperatura Alta , Hiperalgesia/induzido quimicamente , Hiperalgesia/fisiopatologia , Indometacina/farmacologia , Inflamação/induzido quimicamente , Masculino , Morfina/farmacologia , Neuralgia/fisiopatologia , Dor/induzido quimicamente , Medição da Dor/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Estimulação Física/efeitos adversos , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/fisiopatologia , Tiofenos/farmacologia , Ácido gama-Aminobutírico/farmacologia
8.
J Pharmacol Exp Ther ; 331(2): 598-608, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19671883

RESUMO

The presenilin containing gamma-secretase complex is responsible for the regulated intramembraneous proteolysis of the amyloid precursor protein (APP), the Notch receptor, and a multitude of other substrates. gamma-Secretase catalyzes the final step in the generation of Abeta(40) and Abeta(42) peptides from APP. Amyloid beta-peptides (Abeta peptides) aggregate to form neurotoxic oligomers, senile plaques, and congophilic angiopathy, some of the cardinal pathologies associated with Alzheimer's disease. Although inhibition of this protease acting on APP may result in potentially therapeutic reductions of neurotoxic Abeta peptides, nonselective inhibition of the enzyme may cause severe adverse events as a result of impaired Notch receptor processing. Here, we report the preclinical pharmacological profile of GSI-953 (begacestat), a novel thiophene sulfonamide gamma-secretase inhibitor (GSI) that selectively inhibits cleavage of APP over Notch. This GSI inhibits Abeta production with low nanomolar potency in cellular and cell-free assays of gamma-secretase function, and displaces a tritiated analog of GSI-953 from enriched gamma-secretase enzyme complexes with similar potency. Cellular assays of Notch cleavage reveal that this compound is approximately 16-fold selective for the inhibition of APP cleavage. In the human APP-overexpressing Tg2576 transgenic mouse, treatment with this orally active compound results in a robust reduction in brain, plasma, and cerebral spinal fluid Abeta levels, and a reversal of contextual fear-conditioning deficits that are correlated with Abeta load. In healthy human volunteers, oral administration of a single dose of GSI-953 produces dose-dependent changes in plasma Abeta levels, confirming pharmacodynamic activity of GSI-953 in humans.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Adolescente , Adulto , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Ligação Competitiva , Células CHO , Linhagem Celular , Cricetinae , Cricetulus , Cães , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/toxicidade , Medo/psicologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Ratos , Ratos Sprague-Dawley , Receptores Notch/fisiologia , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacocinética , Sulfonamidas/toxicidade , Tiofenos/farmacocinética , Tiofenos/toxicidade , Adulto Jovem
9.
Life Sci ; 85(11-12): 450-6, 2009 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-19632245

RESUMO

AIMS: We sought to investigate effects of local and systemic inflammation on CNS permeability of small molecules and compare these to effects of direct injury to the nervous system. MAIN METHODS: Evans blue was used to determine the integrity of the blood-brain barrier (BBB) following local inflammation, systemic inflammation, injury to the L5 spinal nerve or transient occlusion of the middle cerebral artery. In addition, three compounds having low, medium and high brain permeability (atenolol, morphine and oxycodone, respectively) were used. Following model establishment (4-hr post-carrageenan, 24-hr post-FCA, 2-, 4- and 24-hr post-LPS, 21 days post-nerve injury) compounds were administered and 30 min later the brain, spinal cord and blood removed. The plasma and tissue concentrations of compounds were quantified by LC/MS/MS. KEY FINDINGS: Localized inflammation did not affect Evans blue penetration into the CNS but significantly increased morphine penetration into the spinal cord. Systemic inflammation increased the quantity of Evans blue in the CNS but also decreased the penetration of atenolol, morphine and oxycodone into the brain 4-hr post-insult. Nerve injury had no effect on Evans blue or compound penetration, while middle cerebral artery occlusion resulted in a large but short lived increase in Evans blue penetration into both the cortex and striatum. SIGNIFICANCE: The presence of inflammation may affect the CNS penetration of some compounds but is unlikely to lead to a large non-selective BBB breakdown. As a result, it is appropriate to test for side-effects, and conduct brain pharmacokinetic determinations, in naïve rats.


Assuntos
Sistema Nervoso Central/lesões , Sistema Nervoso Central/metabolismo , Inflamação/metabolismo , Antagonistas Adrenérgicos beta/metabolismo , Animais , Artrite Experimental/metabolismo , Atenolol/metabolismo , Química Encefálica/efeitos dos fármacos , Carragenina , Sistema Nervoso Central/patologia , Edema/induzido quimicamente , Edema/patologia , Edema/prevenção & controle , Adjuvante de Freund , Inflamação/patologia , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/toxicidade , Masculino , Artéria Cerebral Média/fisiologia , Morfina/farmacologia , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Nervos Espinhais/lesões , Nervos Espinhais/patologia
10.
Bioorg Med Chem ; 17(13): 4708-17, 2009 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-19443228

RESUMO

gamma-Secretase inhibitors have been shown to reduce the production of beta-amyloid, a component of the plaques that are found in brains of patients with Alzheimer's disease. A novel series of heterocyclic sulfonamide gamma-secretase inhibitors that reduce beta-amyloid levels in cells is reported. Several examples of compounds within this series demonstrate a higher propensity to inhibit the processing of amyloid precursor protein compared to Notch, an alternative gamma-secretase substrate.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Células CHO , Cricetinae , Cricetulus , Compostos Heterocíclicos/síntese química , Humanos , Estrutura Molecular , Ligação Proteica , Receptores Notch/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química
11.
Bioorg Med Chem Lett ; 19(3): 926-9, 2009 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-19097890

RESUMO

Accumulation of beta-amyloid (Abeta), produced by the proteolytic cleavage of amyloid precursor protein (APP) by beta- and gamma-secretase, is widely believed to be associated with Alzheimer's disease (AD). Research around the high-throughput screening hit (S)-4-chlorophenylsulfonyl isoleucinol led to the identification of the Notch-1-sparing (9.5-fold) gamma-secretase inhibitor (S)-N-(5-chlorothiophene-2-sulfonyl)-beta,beta-diethylalaninol 7.b.2 (Abeta(40/42) EC(50)=28 nM), which is efficacious in reduction of Abeta production in vivo.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Isoleucina/análogos & derivados , Receptor Notch1/metabolismo , Álcoois , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/química , Animais , Desenho de Fármacos , Humanos , Isoleucina/química , Modelos Químicos , Propanolaminas/química , Sulfonamidas/química
12.
J Med Chem ; 51(23): 7348-51, 2008 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-19012391

RESUMO

SAR on HTS hits 1 and 2 led to the potent, Notch-1-sparing GSI 9, which lowered brain Abeta in Tg2576 mice at 100 mg/kg po. Converting the metabolically labile methyl groups in 9 to trifluoromethyl groups afforded the more stable analogue 10, which had improved in vivo potency. Further side chain modification afforded the potent Notch-1-sparing GSI begacestat (5), which was selected for development for the treatment of Alzheimer's disease.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Receptor Notch1/metabolismo , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Doença de Alzheimer/enzimologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Cristalografia por Raios X , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Camundongos , Camundongos Transgênicos , Modelos Moleculares , Conformação Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Tiofenos/síntese química , Tiofenos/química
13.
Pain ; 140(3): 436-445, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18945547

RESUMO

Clinically, pain is a complex phenomenon consisting of both sensory and affective aberrations that can persist indefinitely. Pre-clinically, several animal paradigms have been established that reliably mimic both the acute and chronic aspects of pain pertinent to the human condition; however, the commonly used behavioral models only assess the sensory component of pain elicited by an evoked nociceptive stimulus. Since the affective-motivational component of pain is an important determinant of the overall pain experience in man, we investigated how this aspect may be modeled long-term in rats using novel objects and a modified conditioned place aversion (CPA) paradigm. Findings demonstrate that animals subjected to either neuropathic injury or inflammatory insult display a significant conditioned place aversion to a pain-paired environment that is paralleled by an increased number of hind paw withdrawals and fewer number of novel object interactions during painful conditioning sessions. Moreover, this aversion is maintained for 1 month in the absence of further conditioning. We also determined that a non-analgesic, non-rewarding dose of morphine administered prior to pain-paired conditioning sessions attenuates the pain-induced aversion and its relative persistence in both pain models. Together, these findings underscore the importance of negative affect accompanying painful conditions and its long-term persistence even when the injury or insult has resolved. Lastly, these results suggest how both sensory and affective aberrations associated with neuropathic- and inflammatory-like conditions and the memory of such known to impact quality of life in man may be addressed pre-clinically in rodents.


Assuntos
Transtornos de Ansiedade/psicologia , Transtorno Depressivo/psicologia , Transtornos do Humor/psicologia , Dor/psicologia , Estresse Psicológico/psicologia , Doença Aguda/psicologia , Analgésicos Opioides/farmacologia , Animais , Transtornos de Ansiedade/etiologia , Transtornos de Ansiedade/fisiopatologia , Aprendizagem da Esquiva/fisiologia , Carragenina , Doença Crônica/psicologia , Condicionamento Psicológico/fisiologia , Transtorno Depressivo/etiologia , Transtorno Depressivo/fisiopatologia , Modelos Animais de Doenças , Inflamação/induzido quimicamente , Inflamação/fisiopatologia , Inflamação/psicologia , Mediadores da Inflamação , Transtornos do Humor/etiologia , Transtornos do Humor/fisiopatologia , Morfina/farmacologia , Dor/complicações , Dor/fisiopatologia , Ratos , Estresse Psicológico/etiologia , Estresse Psicológico/fisiopatologia , Tempo
15.
J Pharmacol Exp Ther ; 322(3): 1294-304, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17586724

RESUMO

Here, we have investigated the in vitro pharmacology of a muscarinic agonist, (3R,4R)-3-(3-hexylsulfanyl-pyrazin-2-yloxy)-1-aza-bicyclo[2.2.1]heptane (WAY-132983), and we demonstrated its activity in several models of pain. WAY-132983 had a similar affinity for the five muscarinic receptors (9.4-29.0 nM); however, in calcium mobilization studies it demonstrated moderate selectivity for M(1) (IC(50) = 6.6 nM; E(max) = 65% of 10 muM carbachol-stimulation) over the M(3) (IC(50) = 23 nM; E(max) = 41%) and M(5) receptors (IC(50) = 300 nM; E(max) = 18%). WAY-132983 also activated the M(4) receptor, fully inhibiting forskolin-induced increase in cAMP levels (IC(50) = 10.5 nM); at the M(2) receptor its potency was reduced by 5-fold (IC(50) = 49.8 nM). In vivo, WAY-132983 demonstrated good systemic bioavailability and high brain penetration (>20-fold over plasma levels). In addition, WAY-1329823 produced potent and efficacious antihyperalgesic and antiallodynic effects in rodent models of chemical irritant, chronic inflammatory, neuropathic, and incisional pain. It is noteworthy that efficacy in these models was observed at doses that did not produce analgesia or ataxia. Furthermore, a series of antagonist studies demonstrated that the in vivo activity of WAY-132983 is mediated through activation of muscarinic receptors primarily through the M(4) receptor. The data presented herein suggest that muscarinic agonists, such as WAY-132983, may have a broad therapeutic efficacy for the treatment of pain.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/farmacocinética , Agonistas Muscarínicos/farmacologia , Dor/prevenção & controle , Pirazinas/farmacocinética , Animais , Disponibilidade Biológica , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Doença Crônica , Modelos Animais de Doenças , Inflamação , Concentração Inibidora 50 , Pirazinas/farmacologia , Ratos , Receptores Muscarínicos
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