Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 29
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Pharmacol Toxicol Methods ; 94(Pt 1): 34-43, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29684554

RESUMO

INTRODUCTION: The adenine model of kidney disease typically involves dietary delivery of adenine over several weeks. This model can be variable in its disease progression and can result in significant mortality. In the current study, the amount of adenine delivered to rats was controlled by utilizing oral gavage administration over a short period in an attempt to induce robust renal pathology while addressing variability and viability of the animals. METHODS: Adenine (150 or 200 mg/kg) was administered via oral gavage for 10 consecutive days, and assessed over a total of 20 days. RESULTS: Both adenine dose groups manifested pathophysiological features of kidney disease such as proteinuria, elevated serum creatinine and BUN, and tubulointerstitial fibrosis. The animals also displayed a decline in glomerular filtration rate. Renal mRNA expression of genes associated with injury, inflammation, and fibrosis (i.e., Col1a1, Acta2, Serpine1, Timp1, Fn-Eda, Tgfb1, Ccl2, Nlrp3, Aqp1 and Ccnd1) were elevated as were urinary biomarkers that have translational utility (i.e., clusterin, KIM-1, MCP-1, OPN, NGAL, B2M, calbindin, and cystatin C). All disease endpoints were more pronounced in the 200 mg/kg group, however, while measures of tissue fibrosis were sustained, there was partial recovery by day 20 in functional readouts. No mortality was observed in either dose group. DISCUSSION: Short-term delivery of adenine via precise gavage delivery induced a robust model with hallmarks of fibrotic kidney disease, had limited variance between animals, and no animal morbidity within the 20 days studied. This model represents a methodical alternative to long-term dietary dosing of adenine.


Assuntos
Adenina/administração & dosagem , Fibrose/induzido quimicamente , Nefropatias/induzido quimicamente , Rim/efeitos dos fármacos , Administração Oral , Animais , Biomarcadores/urina , Fibrose/metabolismo , Fibrose/urina , Taxa de Filtração Glomerular/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/urina , Rim/metabolismo , Nefropatias/metabolismo , Nefropatias/urina , Masculino , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley
2.
J Am Soc Nephrol ; 28(12): 3616-3626, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28827403

RESUMO

Targeted delivery of a therapeutic agent to a site of pathology to ameliorate disease while limiting exposure at undesired tissues is an aspirational treatment scenario. Targeting diseased kidneys for pharmacologic treatment has had limited success. We designed an approach to target an extracellular matrix protein, the fibronectin extra domain A isoform (FnEDA), which is relatively restricted in distribution to sites of tissue injury. In a mouse unilateral ureteral obstruction (UUO) model of renal fibrosis, injury induced significant upregulation of FnEDA in the obstructed kidney. Using dual variable domain Ig (DVD-Ig) technology, we constructed a molecule with a moiety to target FnEDA and a second moiety to neutralize TGF-ß After systemic injection of the bispecific TGF-ß + FnEDA DVD-Ig or an FnEDA mAb, chemiluminescent detection and imaging with whole-body single-photon emission computed tomography (SPECT) revealed significantly higher levels of each molecule in the obstructed kidney than in the nonobstructed kidney, the ipsilateral kidney of sham animals, and other tissues. In comparison, a systemically administered TGF-ß mAb accumulated at lower concentrations in the obstructed kidney and exhibited a more diffuse whole-body distribution. Systemic administration of the bispecific DVD-Ig or the TGF-ß mAb (1-10 mg/kg) but not the FnEDA mAb attenuated the injury-induced collagen deposition detected by immunohistochemistry and elevation in Col1a1, FnEDA, and TIMP1 mRNA expression in the obstructed kidney. Overall, systemic delivery of a bispecific molecule targeting an extracellular matrix protein and delivering a TGF-ß mAb resulted in a relatively focal uptake in the fibrotic kidney and reduced renal fibrosis.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Nefropatias/tratamento farmacológico , Rim/efeitos dos fármacos , Fator de Crescimento Transformador beta/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Matriz Extracelular/metabolismo , Fibronectinas/química , Fibrose/tratamento farmacológico , Humanos , Hibridomas/metabolismo , Rim/diagnóstico por imagem , Rim/patologia , Masculino , Camundongos , Tomografia Computadorizada de Emissão de Fóton Único , Ureter/patologia
3.
Eur J Pharmacol ; 788: 1-11, 2016 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-27288879

RESUMO

Adenosine (ADO) is an important regulatory purine nucleoside that accumulates at sites of inflammation and tissue injury including in diseases associated with renal pathology. Endogenous levels of ADO may be increased by inhibiting the ADO-metabolizing enzyme, ADO kinase (AK). AK inhibitors have demonstrated protection in rodent models of diabetic nephropathy. To further investigate AK inhibition as a potential mechanism for renal protection, A-306989, a potent non-nucleoside AK inhibitor, was examined in both in vitro and in vivo assays of renal injury. A-306989 prevented podocyte damage (disruption of actin cytoskeleton) and increased podocyte survival following puromycin aminonucleoside (PAN) application in both mouse and human conditionally immortalized podocytes. Prophylactic oral administration of A-306989 (1.5, 5 and 15mg/kg) reduced proteinuria in a dose-dependent manner and repressed pro-inflammatory/fibrotic gene up-regulation; A-306989 was also efficacious when administered two days following the PAN-insult. A-306989 (10 and 30mg/kg) also significantly reduced proteinuria and macrophage infiltration in a rat model of glomerulonephritis. Finally, A-306989 (15 and 50mg/kg) reduced the expression levels of pro-inflammatory/fibrotic genes, and reduced macrophage infiltration (50mg/kg), but did not affect the deposition of interstitial collagen in fibrotic kidneys from mice with unilateral ureter obstruction. A-306989 also had beneficial actions on "quality of life" measures including improving body weight loss. Thus, these data indicate that enhancement of endogenous ADO levels by A-306989 can positively modulate renal pathology and mimic some of the previously reported beneficial actions of ADO A2A receptor agonists.


Assuntos
Adenosina Quinase/antagonistas & inibidores , Membrana Basal/diagnóstico por imagem , Citoproteção/efeitos dos fármacos , Rim/citologia , Rim/lesões , Podócitos/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Animais , Fibrose , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Camundongos , Podócitos/citologia , Podócitos/metabolismo , Puromicina Aminonucleosídeo/toxicidade , Ratos
4.
J Neurophysiol ; 111(2): 394-404, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24155005

RESUMO

N-, T- and P/Q-type voltage-gated Ca(2+) channels are critical for regulating neurotransmitter release and cellular excitability and have been implicated in mediating pathological nociception. A-1264087 is a novel state-dependent blocker of N-, T- and P/Q-type channels. In the present studies, A-1264087 blocked (IC50 = 1.6 µM) rat dorsal root ganglia N-type Ca(2+) in a state-dependent fashion. A-1264087 (1, 3 and 10 mg/kg po) dose-dependently reduced mechanical allodynia in rats with a spinal nerve ligation (SNL) injury. A-1264087 (4 mg/kg iv) inhibited both spontaneous and mechanically evoked activity of spinal wide dynamic range (WDR) neurons in SNL rats but had no effect in uninjured rats. The inhibitory effect on WDR neurons remained in spinally transected SNL rats. Injection of A-1264087 (10 nmol/0.5 µl) into the spinal cord reduced both spontaneous and evoked WDR activity in SNL rats. Application of A-1264087 (300 nmol/20 µl) into the receptive field on the hindpaw attenuated evoked but not spontaneous firing of WDR neurons. Using electrical stimulation, A-1264087 (4 mg/kg iv) inhibited Aδ- and C-fiber evoked responses and after-discharge of WDR neurons in SNL rats. These effects by A-1264087 were not present in uninjured rats. A-1264087 moderately attenuated WDR neuron windup in both uninjured and SNL rats. In summary, these results indicate that A-1264087 selectively inhibited spinal nociceptive transmission in sensitized states through both peripheral and central mechanisms.


Assuntos
Anestésicos/farmacologia , Compostos Azabicíclicos/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Leucina/análogos & derivados , Neuralgia/fisiopatologia , Nociceptividade/efeitos dos fármacos , Nervos Periféricos/efeitos dos fármacos , Nervos Espinhais/efeitos dos fármacos , Potenciais de Ação , Administração Cutânea , Anestésicos/administração & dosagem , Anestésicos/uso terapêutico , Animais , Compostos Azabicíclicos/uso terapêutico , Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/uso terapêutico , Relação Dose-Resposta a Droga , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Concentração Inibidora 50 , Injeções Espinhais , Leucina/farmacologia , Leucina/uso terapêutico , Masculino , Neuralgia/tratamento farmacológico , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Nervos Periféricos/fisiologia , Ratos , Ratos Sprague-Dawley , Nervos Espinhais/fisiologia
5.
J Pain ; 15(4): 387.e1-14, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24374196

RESUMO

UNLABELLED: Voltage-gated Ca(2+) channels play an important role in nociceptive transmission. There is significant evidence supporting a role for N-, T- and P/Q-type Ca(2+) channels in chronic pain. Here, we report that A-1264087, a structurally novel state-dependent blocker, inhibits each of these human Ca(2+) channels with similar potency (IC50 = 1-2 µM). A-1264087 was also shown to inhibit the release of the pronociceptive calcitonin gene-related peptide from rat dorsal root ganglion neurons. Oral administration of A-1264087 produces robust antinociceptive efficacy in monoiodoacetate-induced osteoarthritic, complete Freund adjuvant-induced inflammatory, and chronic constrictive injury of sciatic nerve-induced, neuropathic pain models with ED50 values of 3.0, 5.7, and 7.8 mg/kg (95% confidence interval = 2.2-3.5, 3.7-10, and 5.5-12.8 mg/kg), respectively. Further analysis revealed that A-1264087 also suppressed nociceptive-induced p38 and extracellular signal-regulated kinase 1/2 phosphorylation, which are biochemical markers of engagement of pain circuitry in chronic pain states. Additionally, A-1264087 inhibited both spontaneous and evoked neuronal activity in the spinal cord dorsal horn in complete Freund adjuvant-inflamed rats, providing a neurophysiological basis for the observed antihyperalgesia. A-1264087 produced no alteration of body temperature or motor coordination and no learning impairment at therapeutic plasma concentrations. PERSPECTIVE: The present results demonstrate that the neuronal Ca(2+) channel blocker A-1264087 exhibits broad-spectrum efficacy through engagement of nociceptive signaling pathways in preclinical pain models in the absence of effects on psychomotor and cognitive function.


Assuntos
Analgésicos/farmacologia , Compostos Azabicíclicos/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Leucina/análogos & derivados , Neurônios/metabolismo , Nociceptividade/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Imuno-Histoquímica , Leucina/farmacologia , Masculino , Neurônios/efeitos dos fármacos , Dor/metabolismo , Técnicas de Patch-Clamp , Ratos Sprague-Dawley , Medula Espinal/metabolismo
7.
Bioorg Med Chem ; 20(13): 4128-39, 2012 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-22626552

RESUMO

A novel 4-aminocyclopentapyrrolidine series of N-type Ca(2+) channel blockers have been discovered. Enantioselective synthesis of the 4-aminocyclopentapyrrolidines was enabled using N-tert-butyl sulfinamide chemistry. SAR studies demonstrate selectivity over L-type Ca(2+) channels. N-type Ca(2+) channel blockade was confirmed using electrophysiological recording techniques. Compound 25 is an N-type Ca(2+) channel blocker that produces antinociception in inflammatory and nociceptive pain models without exhibiting cardiovascular or motor liabilities.


Assuntos
Acetamidas/síntese química , Analgésicos/síntese química , Bloqueadores dos Canais de Cálcio/síntese química , Canais de Cálcio Tipo N/química , Pirrolidinas/química , Pirrolidinas/síntese química , Acetamidas/farmacologia , Acetamidas/uso terapêutico , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Comportamento Animal/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio Tipo N/metabolismo , Modelos Animais de Doenças , Masculino , Dor/tratamento farmacológico , Pirrolidinas/farmacologia , Pirrolidinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
8.
Biochem Pharmacol ; 83(3): 406-18, 2012 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-22153861

RESUMO

Blockade of voltage-gated Ca²âº channels on sensory nerves attenuates neurotransmitter release and membrane hyperexcitability associated with chronic pain states. Identification of small molecule Ca²âº channel blockers that produce significant antinociception in the absence of deleterious hemodynamic effects has been challenging. In this report, two novel structurally related compounds, A-686085 and A-1048400, were identified that potently block N-type (IC50=0.8 µM and 1.4 µM, respectively) and T-type (IC50=4.6 µM and 1.2 µM, respectively) Ca²âº channels in FLIPR based Ca²âº flux assays. A-686085 also potently blocked L-type Ca²âº channels (EC50=0.6 µM), however, A-1048400 was much less active in blocking this channel (EC50=28 µM). Both compounds dose-dependently reversed tactile allodynia in a model of capsaicin-induced secondary hypersensitivity with similar potencies (EC50=300-365 ng/ml). However, A-686085 produced dose-related decreases in mean arterial pressure at antinociceptive plasma concentrations in the rat, while A-1048400 did not significantly alter hemodynamic function at supra-efficacious plasma concentrations. Electrophysiological studies demonstrated that A-1048400 blocks native N- and T-type Ca²âº currents in rat dorsal root ganglion neurons (IC50=3.0 µM and 1.6 µM, respectively) in a voltage-dependent fashion. In other experimental pain models, A-1048400 dose-dependently attenuated nociceptive, neuropathic and inflammatory pain at doses that did not alter psychomotor or hemodynamic function. The identification of A-1048400 provides further evidence that voltage-dependent inhibition of neuronal Ca²âº channels coupled with pharmacological selectivity vs. L-type Ca²âº channels can provide robust antinociception in the absence of deleterious effects on hemodynamic or psychomotor function.


Assuntos
Analgésicos/administração & dosagem , Bloqueadores dos Canais de Cálcio/administração & dosagem , Hemodinâmica/fisiologia , Neurônios/fisiologia , Medição da Dor , Piperidonas/administração & dosagem , Piperidonas/química , Administração Oral , Animais , Relação Dose-Resposta a Droga , Células HEK293 , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Neurônios/efeitos dos fármacos , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Ratos , Ratos Sprague-Dawley
9.
Biochem Pharmacol ; 82(8): 967-76, 2011 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-21620806

RESUMO

Positive modulation of the neuronal nicotinic acetylcholine receptor (nAChR) α4ß2 subtype by selective positive allosteric modulator NS-9283 has shown to potentiate the nAChR agonist ABT-594-induced anti-allodynic activity in preclinical neuropathic pain. To determine whether this benefit can be extended beyond neuropathic pain, the present study examined the analgesic activity and adverse effect profile of co-administered NS-9283 and ABT-594 in a variety of preclinical models in rats. The effect of the combined therapy on drug-induced brain activities was also determined using pharmacological magnetic resonance imaging. In carrageenan-induced thermal hyperalgesia, co-administration of NS-9283 (3.5 µmol/kg, i.p.) induced a 6-fold leftward shift of the dose-response of ABT-594 (ED(50)=26 vs. 160 nmol/kg, i.p.). In the paw skin incision model of post-operative pain, co-administration of NS-9283 similarly induced a 6-fold leftward shift of ABT-594 (ED(50)=26 vs. 153 nmol/kg). In monoiodo-acetate induced knee joint pain, co-administration of NS-9283 enhanced the potency of ABT-594 by 5-fold (ED(50)=1.0 vs. 4.6 nmol/kg). In pharmacological MRI, co-administration of NS-9283 was shown to lead to a leftward shift of ABT-594 dose-response for cortical activation. ABT-594 induced CNS-related adverse effects were not exacerbated in presence of an efficacious dose of NS-9283 (3.5 µmol/kg). Acute challenge of NS-9283 produced no cross sensitization in nicotine-conditioned animals. These results demonstrate that selective positive allosteric modulation at the α4ß2 nAChR potentiates nAChR agonist-induced analgesic activity across neuropathic and nociceptive preclinical pain models without potentiating ABT-594-mediated adverse effects, suggesting that selective positive modulation of α4ß2 nAChR by PAM may represent a novel analgesic approach.


Assuntos
Analgésicos/uso terapêutico , Azetidinas/uso terapêutico , Agonistas Nicotínicos/uso terapêutico , Oxidiazóis/uso terapêutico , Dor/tratamento farmacológico , Piridinas/uso terapêutico , Receptores Nicotínicos/metabolismo , Regulação Alostérica , Analgésicos/administração & dosagem , Analgésicos/efeitos adversos , Animais , Azetidinas/administração & dosagem , Azetidinas/efeitos adversos , Comportamento Animal/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Quimioterapia Combinada , Imageamento por Ressonância Magnética , Masculino , Agonistas Nicotínicos/administração & dosagem , Agonistas Nicotínicos/efeitos adversos , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Oxidiazóis/administração & dosagem , Oxidiazóis/efeitos adversos , Dor/metabolismo , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Ratos , Ratos Sprague-Dawley
10.
Br J Pharmacol ; 162(2): 428-40, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20880025

RESUMO

BACKGROUND AND PURPOSE: Cannabinoid CB2 receptor activation by selective agonists has been shown to produce analgesic effects in preclinical models of inflammatory and neuropathic pain. However, mechanisms underlying CB2-mediated analgesic effects remain largely unknown. The present study was conducted to elucidate the CB2 receptor expression in 'pain relevant' tissues and the potential sites of action of CB2 agonism in rats. EXPERIMENTAL APPROACH: Expression of cannabinoid receptor mRNA was evaluated by quantitative RT-PCR in dorsal root ganglia (DRGs), spinal cords, paws and several brain regions of sham, chronic inflammatory pain (CFA) and neuropathic pain (spinal nerve ligation, SNL) rats. The sites of CB2 mediated antinociception were evaluated in vivo following intra-DRG, intrathecal (i.t.) or intraplantar (i.paw) administration of potent CB2-selective agonists A-836339 and AM1241. KEY RESULTS: CB2 receptor gene expression was significantly up-regulated in DRGs (SNL and CFA), spinal cords (SNL) or paws (CFA) ipsilateral to injury under inflammatory and neuropathic pain conditions. Systemic A-836339 and AM1241 produced dose-dependent efficacy in both inflammatory and neuropathic pain models. Local administration of CB2 agonists also produced significant analgesic effects in SNL (intra-DRG and i.t.) and CFA (intra-DRG) pain models. In contrast to A-836339, i.paw administration of AM-1241 dose-relatedly reversed the CFA-induced thermal hyperalgesia, suggesting that different mechanisms may be contributing to its in vivo properties. CONCLUSIONS AND IMPLICATIONS: These results demonstrate that both DRG and spinal cord are important sites contributing to CB2 receptor-mediated analgesia and that the changes in CB2 receptor expression play a crucial role for the sites of action in regulating pain perception.


Assuntos
Analgésicos/farmacologia , Neuralgia/tratamento farmacológico , Dor/tratamento farmacológico , Receptor CB2 de Canabinoide/metabolismo , Analgesia , Analgésicos/uso terapêutico , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Canabinoides/farmacologia , Canabinoides/uso terapêutico , Modelos Animais de Doenças , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Masculino , Neuralgia/induzido quimicamente , Peptídeos Opioides/metabolismo , Dor/metabolismo , Percepção da Dor , RNA Mensageiro/análise , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Receptor CB2 de Canabinoide/agonistas , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Tiazóis/farmacologia , Tiazóis/uso terapêutico
11.
Pharmacol Biochem Behav ; 95(1): 41-50, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20004681

RESUMO

The histamine H(4) receptor (H(4)R) is expressed primarily on cells involved in inflammation and immune responses. To determine the potential role of H(4)R in pain transmission, the effects of JNJ7777120, a potent and selective H(4) antagonist, were characterized in preclinical pain models. Administration of JNJ7777120 fully blocked neutrophil influx observed in a mouse zymosan-induced peritonitis model (ED(50)=17 mg/kg s.c., 95% CI=8.5-26) in a mast cell-dependent manner. JNJ7777120 potently reversed thermal hyperalgesia observed following intraplantar carrageenan injection of acute inflammatory pain (ED(50)=22 mg/kg i.p., 95% CI=10-35) in rats and significantly decreased the myeloperoxide activity in the carrageenan-injected paw. In contrast, no effects were produced by either H(1)R antagonist diphenhydramine, H(2)R antagonists ranitidine, or H(3)R antagonist ABT-239. JNJ7777120 also exhibited robust anti-nociceptive activity in persistent inflammatory (CFA) pain with an ED(50) of 29 mg/kg i.p. (95% CI=19-40) and effectively reversed monoiodoacetate (MIA)-induced osteoarthritic joint pain. This compound also produced dose-dependent anti-allodynic effects in the spinal nerve ligation (ED(50)=60 mg/kg) and sciatic nerve constriction injury (ED(50)=88 mg/kg) models of chronic neuropathic pain, as well as in a skin-incision model of acute post-operative pain (ED(50)=68 mg/kg). In addition, the analgesic effects of JNJ7777120 were maintained following repeated administration and were evident at the doses that did not cause neurologic deficits in rotarod test. Our results demonstrate that selective blockade of H(4) receptors in vivo produces significant anti-nociception in animal models of inflammatory and neuropathic pain.


Assuntos
Analgésicos/farmacologia , Modelos Animais de Doenças , Inflamação/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Analgésicos/uso terapêutico , Animais , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ensaio Radioligante , Ratos , Receptores Histamínicos , Receptores Histamínicos H4
12.
J Med Chem ; 53(1): 295-315, 2010 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-19921781

RESUMO

Several 3-acylindoles with high affinity for the CB(2) cannabinoid receptor and selectivity over the CB(1) receptor have been prepared. A variety of 3-acyl substituents were investigated, and the tetramethylcyclopropyl group was found to lead to high affinity CB(2) agonists (5, 16). Substitution at the N1-indole position was then examined. A series of aminoalkylindoles was prepared and several substituted aminoethyl derivatives were active (23-27, 5) at the CB(2) receptor. A study of N1 nonaromatic side chain variants provided potent agonists at the CB(2) receptor (16, 35-41, 44-47, 49-54, and 57-58). Several polar side chains (alcohols, oxazolidinone) were well-tolerated for CB(2) receptor activity (41, 50), while others (amide, acid) led to weaker or inactive compounds (55 and 56). N1 aromatic side chains also afforded several high affinity CB(2) receptor agonists (61, 63, 65, and 69) but were generally less potent in an in vitro CB(2) functional assay than were nonaromatic side chain analogues.


Assuntos
Indóis/farmacologia , Cetonas/farmacologia , Receptor CB2 de Canabinoide/agonistas , Desenho de Fármacos , Humanos , Indóis/síntese química , Indóis/química , Cetonas/síntese química , Cetonas/química , Ligantes , Estrutura Molecular , Receptor CB1 de Canabinoide/agonistas , Estereoisomerismo , Relação Estrutura-Atividade
13.
J Pharmacol Exp Ther ; 328(1): 141-51, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18931146

RESUMO

Studies demonstrating the antihyperalgesic and antiallodynic effects of cannabinoid CB(2) receptor activation have been largely derived from the use of receptor-selective ligands. Here, we report the identification of A-836339 [2,2,3,3-tetramethyl-cyclopropanecarboxylic acid [3-(2-methoxy-ethyl)-4,5-dimethyl-3H-thiazol-(2Z)-ylidene]-amide], a potent and selective CB(2) agonist as characterized in in vitro pharmacological assays and in in vivo models of pain and central nervous system (CNS) behavior models. In radioligand binding assays, A-836339 displays high affinities at CB(2) receptors and selectivity over CB(1) receptors in both human and rat. Likewise, A-836339 exhibits high potencies at CB(2) and selectivity over CB(1) receptors in recombinant fluorescence imaging plate reader and cyclase functional assays. In addition A-836339 exhibits a profile devoid of significant affinity at other G-protein-coupled receptors and ion channels. A-836339 was characterized extensively in various animal pain models. In the complete Freund's adjuvant model of inflammatory pain, A-836339 exhibits a potent CB(2) receptor-mediated antihyperalgesic effect that is independent of CB(1) or mu-opioid receptors. A-836339 has also demonstrated efficacies in the chronic constrain injury (CCI) model of neuropathic pain, skin incision, and capsaicin-induced secondary mechanical hyperalgesia models. Furthermore, no tolerance was developed in the CCI model after subchronic treatment with A-836339 for 5 days. In assessing CNS effects, A-836339 exhibited a CB(1) receptor-mediated decrease of spontaneous locomotor activities at a higher dose, a finding consistent with the CNS activation pattern observed by pharmacological magnetic resonance imaging. These data demonstrate that A-836339 is a useful tool for use of studying CB(2) receptor pharmacology and for investigation of the role of CB(2) receptor modulation for treatment of pain in preclinical animal models.


Assuntos
Amidas/farmacologia , Ciclopropanos/farmacologia , Inflamação/fisiopatologia , Dor/fisiopatologia , Receptor CB1 de Canabinoide/fisiologia , Receptor CB2 de Canabinoide/fisiologia , Animais , Células CHO , Linhagem Celular , Cricetinae , Cricetulus , Procedimentos Cirúrgicos Dermatológicos , Membro Posterior , Humanos , Hiperalgesia/fisiopatologia , Rim/embriologia , Imageamento por Ressonância Magnética/métodos , Masculino , Dor Pós-Operatória/fisiopatologia , Desempenho Psicomotor/efeitos dos fármacos , Desempenho Psicomotor/fisiologia , Ratos , Ratos Sprague-Dawley , Receptor CB2 de Canabinoide/agonistas
14.
J Neurophysiol ; 100(6): 3158-66, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18829846

RESUMO

TRPV1 receptors are activated and/or modulated by noxious heat, capsaicin, protons and other endogenous agents released following tissue injury. There is a growing appreciation that this molecular integrator may also have a role in mechanosensation. To further understand this role, we investigated the systemic and site-specific effects of a selective TRPV1 receptor antagonist, A-889425, on low-intensity mechanical stimulation in inflamed rats. Systemic administration of A-889425 (30 and 100 micromol/kg po) reduced mechanical allodynia in complete Freund's adjuvant (CFA)-inflamed rats. Systemic A-889425 (3 and 10 micromol/kg iv) also decreased the responses of spinal wide dynamic range (WDR) neurons to low-intensity mechanical stimulation in CFA-inflamed but not uninjured rats. This effect of A-889425 was likely mediated via multiple sites since local injection of A-889425 into the spinal cord (1-3 nmol), ipsilateral hindpaw (200 nmol), and cerebral ventricles (30-300 nmol) all attenuated WDR responses to low-intensity mechanical stimulation. In addition to an effect on mechanotransmission, systemic administration of A-889425 reduced the spontaneous firing of WDR neurons in inflamed but not uninjured rats. Spontaneous firing is elevated after injury and may reflect ongoing pain in the animal. Local injection experiments indicated that this effect of A-889425 on spontaneous firing was mainly mediated via TRPV1 receptors in the spinal cord. Thus the current data demonstrate that TRPV1 receptors have an enhanced role after an inflammatory injury, impacting both low-intensity mechanotransmission and possibly spontaneous pain. Furthermore this study delineates the differential contribution of central and peripheral TRPV1 receptors to affect spontaneous or mechanically evoked firing of WDR neurons.


Assuntos
Potenciais de Ação/fisiologia , Inflamação/patologia , Neurônios/fisiologia , Medula Espinal/patologia , Canais de Cátion TRPV/fisiologia , Potenciais de Ação/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Potenciais Somatossensoriais Evocados/efeitos dos fármacos , Adjuvante de Freund/farmacologia , Inflamação/induzido quimicamente , Masculino , Neurônios/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Estimulação Física/métodos , Piridinas/química , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Canais de Cátion TRPV/antagonistas & inibidores
15.
Bioorg Med Chem ; 16(12): 6379-86, 2008 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-18501613

RESUMO

The synthesis and pharmacological characterization of a novel furan-based class of voltage-gated sodium channel blockers is reported. Compounds were evaluated for their ability to block the tetrodotoxin-resistant sodium channel Na(v)1.8 (PN3) as well as the Na(v)1.2 and Na(v)1.5 subtypes. Benchmark compounds from this series possessed enhanced potency, oral bioavailability, and robust efficacy in a rodent model of neuropathic pain, together with improved CNS and cardiovascular safety profiles compared to the clinically used sodium channel blockers mexiletine and lamotrigine.


Assuntos
Analgésicos não Narcóticos/química , Analgésicos não Narcóticos/farmacologia , Furanos/química , Furanos/farmacologia , Neuralgia/tratamento farmacológico , Piperazinas/química , Piperazinas/farmacologia , Bloqueadores dos Canais de Sódio/química , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio/efeitos dos fármacos , Analgésicos não Narcóticos/síntese química , Animais , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Furanos/síntese química , Humanos , Masculino , Camundongos , Piperazinas/síntese química , Ratos , Ratos Sprague-Dawley , Bloqueadores dos Canais de Sódio/síntese química , Relação Estrutura-Atividade
16.
J Med Chem ; 51(6): 1904-12, 2008 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-18311894

RESUMO

A series of potent indol-3-yl-tetramethylcyclopropyl ketones have been prepared as CB 2 cannabinoid receptor ligands. Two unsubstituted indoles ( 5, 32) were the starting points for an investigation of the effect of indole ring substitutions on CB 2 and CB 1 binding affinities and activity in a CB 2 in vitro functional assay. Indole ring substitutions had varying effects on CB 2 and CB 1 binding, but were generally detrimental to agonist activity. Substitution on the indole ring did lead to improved CB 2/CB 1 binding selectivity in some cases (i.e., 7- 9, 15- 20). All indoles with the morpholino-ethyl side chain ( 32- 43) exhibited weaker binding affinity and less agonist activity relative to that of their tetrahydropyranyl-methyl analogs ( 5- 31). Several agonists were active in the complete Freund's adjuvant model of chronic inflammatory thermal hyperalgesia ( 32, 15).


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Indóis/farmacologia , Cetonas/farmacologia , Receptor CB2 de Canabinoide/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Ligação Competitiva , Linhagem Celular , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Indóis/síntese química , Indóis/química , Cetonas/síntese química , Cetonas/química , Ligantes , Conformação Molecular , Ratos , Receptor CB1 de Canabinoide/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade
17.
Eur J Pharmacol ; 580(3): 314-21, 2008 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-18054908

RESUMO

Activation of metabotropic glutamate (mGlu) receptors has previously been shown to play a role in inflammatory or neuropathic pain states. However, the role of mGlu type 1 receptors in post-operative pain remains to be investigated. In the present study, effects of potent and selective mGlu1 receptor antagonists A-841720, A-794282, A-794278, and A-850002 were evaluated in a skin incision-induced post-operative pain model in rats. Post-operative pain was examined 2 h following surgery using weight-bearing difference between injured and uninjured paws as a measure of spontaneous pain. In this model, A-841720, A-794282, A-794278, and A-850002 induced significant attenuation of spontaneous post-operative pain behavior, with ED50s of 10, 50, 50, and 65 micromol/kg i.p., respectively. Depending on the compound, significant motor side effects were also observed at 3 to 10 fold higher doses. These results support the notion that mGlu1 receptor activation plays a significant role in nociceptive transmission in post-operative pain, though motor impairment may be a limiting factor in developing mGlu1 receptor antagonists as novel analgesics.


Assuntos
Analgésicos não Narcóticos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Dor Pós-Operatória/prevenção & controle , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Analgésicos não Narcóticos/química , Animais , Cálcio/metabolismo , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Cerebelo/citologia , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Dimetilaminas/química , Dimetilaminas/farmacologia , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/química , Comportamento Exploratório/efeitos dos fármacos , Fluorometria/métodos , Glicina/análogos & derivados , Glicina/farmacologia , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Membro Posterior/cirurgia , Masculino , Estrutura Molecular , Morfina/farmacologia , Dor Pós-Operatória/etiologia , Piridinas/química , Piridinas/farmacologia , Pirimidinonas/química , Pirimidinonas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Resorcinóis/farmacologia , Teste de Desempenho do Rota-Rod/métodos , Tiofenos/química , Tiofenos/farmacologia , Trítio
18.
J Pharmacol Exp Ther ; 319(3): 1376-85, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16982702

RESUMO

ATP-sensitive P2X(7) receptors are localized on cells of immunological origin including glial cells in the central nervous system. Activation of P2X(7) receptors leads to rapid changes in intracellular calcium concentrations, release of the proinflammatory cytokine interleukin-1beta (IL-1beta), and following prolonged agonist exposure, cytolytic plasma membrane pore formation. P2X(7) knockout mice show reduced inflammation as well as decreased nociceptive sensitivity following peripheral nerve injury. A-740003 (N-(1-{[(cyanoimino)(5-quinolinylamino) methyl] amino}-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide) is a novel competitive antagonist of P2X(7) receptors (IC(50) values = 40 nM for human and 18 nM for rat) as measured by agonist-stimulated changes in intracellular calcium concentrations. A-740003 showed weak or no activity (IC(50) > 10 muM) at other P2 receptors and an array of other neurotransmitter and peptide receptors, ion channels, reuptake sites, and enzymes. A-740003 potently blocked agonist-evoked IL-1beta release (IC(50) = 156 nM) and pore formation (IC(50) = 92 nM) in differentiated human THP-1 cells. Systemic administration of A-740003 produced dose-dependent antinociception in a spinal nerve ligation model (ED(50) = 19 mg/kg i.p.) in the rat. A-740003 also attenuated tactile allodynia in two other models of neuropathic pain, chronic constriction injury of the sciatic nerve and vincristine-induced neuropathy. In addition, A-740003 effectively reduced thermal hyperalgesia observed following intraplantar administration of carrageenan or complete Freund's adjuvant (ED(50) = 38-54 mg/kg i.p.). A-740003 was ineffective in attenuating acute thermal nociception in normal rats and did not alter motor performance at analgesic doses. These data demonstrate that selective blockade of P2X(7) receptors in vivo produces significant antinociception in animal models of neuropathic and inflammatory pain.


Assuntos
Acetamidas/farmacologia , Analgésicos , Dor/tratamento farmacológico , Dor/etiologia , Doenças do Sistema Nervoso Periférico/complicações , Antagonistas do Receptor Purinérgico P2 , Quinolinas/farmacologia , Animais , Antineoplásicos Fitogênicos/toxicidade , Cálcio/metabolismo , Linhagem Celular , Corantes , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Edema/tratamento farmacológico , Adjuvante de Freund/farmacologia , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Inflamação/induzido quimicamente , Inflamação/complicações , Inflamação/tratamento farmacológico , Interleucina-1beta/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Nociceptores/efeitos dos fármacos , Equilíbrio Postural/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2X7 , Neuropatia Ciática/prevenção & controle , Nervos Espinhais/lesões , Vincristina/toxicidade
19.
Pain ; 125(1-2): 136-42, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16781071

RESUMO

Gabapentin and pregabalin have been demonstrated, both in animal pain models and clinically, to be effective analgesics particularly for the treatment of neuropathic pain. The precise mechanism of action for these two drugs is unknown, but they are generally believed to function via initially binding to the alpha2delta subunit of voltage-gated Ca2+ channels. In this study, we used a pharmacological approach to test the hypothesis whether high affinity interactions with the alpha2delta subunit alone could lead to attenuation of neuropathic pain in rats. The anti-allodynic effects of gabapentin and pregabalin, along with three other compounds--(L)-phenylglycine, m-chlorophenylglycine and 3-exo-aminobicyclo[2.2.1]heptane-2-exo-carboxylic acid (ABHCA)--discovered to be potent alpha2delta ligands, were tested in the rat spinal nerve ligation model of neuropathic pain. Gabapentin (Ki = 120 nM), pregabalin (180 nM) and (L)-phenylglycine (180 nM) were shown to be anti-allodynic, with respective ED50 values of 230, 90 and 80 micromol/kg (p.o.). (L)-Phenylglycine was as potent as pregabalin and equi-efficacious in reversing mechanical allodynia. In contrast, two ligands with comparable or superior alpha2delta binding affinities, m-chlorophenylglycine (Ki = 54 nM) and ABHCA (150 nM), exhibited no anti-allodynic effects at doses of 30-300 micromol/kg (p.o.), although these compounds achieved substantial brain levels. The data demonstrate that, at least in the rat spinal nerve ligation model of neuropathic pain, (L)-phenylglycine has an anti-allodynic effect, but two equally potent alpha2delta subunit ligands do not. These results suggest that additional mechanisms, besides alpha2delta interactions, may contribute to the effects of compounds like gabapentin, pregabalin and (L)-phenylglycine in neuropathic pain.


Assuntos
Encéfalo/metabolismo , Canais de Cálcio/efeitos dos fármacos , Canais de Cálcio/metabolismo , Glicina/análogos & derivados , Neuralgia/metabolismo , Neuralgia/prevenção & controle , Analgésicos/administração & dosagem , Animais , Encéfalo/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/administração & dosagem , Canais de Cálcio Tipo L , Relação Dose-Resposta a Droga , Glicina/administração & dosagem , Hiperestesia/metabolismo , Hiperestesia/prevenção & controle , Masculino , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento
20.
Eur J Pharmacol ; 531(1-3): 108-17, 2006 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-16438960

RESUMO

Previous studies have demonstrated that Fos-like immunoreactivity is increased in spinal dorsal horn neurons in several pain models, and have suggested that Fos-like immunoreactivity could be used as a marker of neurons activated by painful stimulation. In the present study, we evaluated nociceptive behaviors and spinal Fos-like immunoreactivity in a rat skin incision model of post-operative pain. In this model, evoked and non-evoked pain behaviors were observed at least for 2 days after paw surgery, an increased number of Fos-like immunoreactive neurons was observed in the spinal dorsal horn at lumbar levels 4-5 two-hour post-surgery. The number of Fos-like immunoreactive neurons was significantly greater in animals with skin-muscle incision compared to animals with skin-alone incision. Interestingly, spinal Fos-like immunoreactivity was quickly normalized in rats with paw surgery at later time points (8 and 24 h post-surgery), whereas nociceptive behaviors were still observed. Furthermore, at 24 h post-surgery, spinal Fos-like immunoreactivity induced by thermal stimulation (42, 44, 46, 48, 52 degrees C for 15 s) was not significantly different between sham animals and animals with surgery. In both groups, an increase in spinal Fos-like immunoreactive neurons was observed with increasing temperatures, with similar laminar distribution. Finally, systemic morphine reduced post-operative pain and Fos-like immunoreactivity in a naloxone reversible manner, with greater potency and efficacy on behavioral endpoints than on Fos-like immunoreactivity. These results demonstrate a different profile of nociceptive behaviors and spinal Fos-like immunoreactivity in the rat skin incision model, suggesting a limited potential of spinal Fos-like immunoreactivity to study post-surgical pain and its pharmacology.


Assuntos
Dor Pós-Operatória/fisiopatologia , Células do Corno Posterior/química , Proteínas Proto-Oncogênicas c-fos/análise , Medula Espinal/química , Analgésicos Opioides/farmacologia , Animais , Procedimentos Cirúrgicos Dermatológicos , Relação Dose-Resposta a Droga , Membro Posterior/cirurgia , Imuno-Histoquímica , Masculino , Morfina/farmacologia , Músculos/cirurgia , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Dor Pós-Operatória/prevenção & controle , Células do Corno Posterior/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Medula Espinal/efeitos dos fármacos , Temperatura , Fatores de Tempo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...