Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
Más filtros











Base de datos
Intervalo de año de publicación
1.
Bioorg Med Chem Lett ; 18(19): 5280-4, 2008 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-18783943

RESUMEN

We describe here orally active and brain-penetrant cathepsin S selective inhibitors, which are virtually devoid of hERG K(+) channel affinity, yet exhibit nanomolar potency against cathepsin S and over 100-fold selectivity to cathepsin L. The new non-peptidic inhibitors are based on a 2-cyanopyrimidine scaffold bearing a spiro[3.5]non-6-yl-methyl amine at the 4-position. The brain-penetrating cathepsin S inhibitors demonstrate potential clinical utility for the treatment of multiple sclerosis and neuropathic pain.


Asunto(s)
Catepsinas/antagonistas & inhibidores , Canales de Potasio Éter-A-Go-Go/metabolismo , Pirimidinas/síntesis química , Pirimidinas/farmacología , Administración Oral , Animales , Encéfalo/efectos de los fármacos , Catepsina L , Técnicas Químicas Combinatorias , Cisteína Endopeptidasas , Humanos , Masculino , Estructura Molecular , Esclerosis Múltiple/tratamiento farmacológico , Dolor/tratamiento farmacológico , Pirimidinas/sangre , Pirimidinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad
3.
J Med Chem ; 50(16): 3851-6, 2007 Aug 09.
Artículo en Inglés | MEDLINE | ID: mdl-17630726

RESUMEN

Selective activation of peripheral cannabinoid CB1 receptors has the potential to become a valuable therapy for chronic pain conditions as long as central nervous system effects are attenuated. A new class of cannabinoid ligands was rationally designed from known aminoalkylindole agonists and showed good binding and functional activities at human CB1 and CB2 receptors. This has led to the discovery of a novel CB1/CB2 dual agonist, naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone (13), which displays good oral bioavailability, potent antihyperalgesic activity in animal models, and limited brain penetration.


Asunto(s)
Analgésicos/síntesis química , Encéfalo/metabolismo , Hiperalgesia/tratamiento farmacológico , Naftalenos/síntesis química , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB2/agonistas , Administración Oral , Analgésicos/farmacocinética , Analgésicos/farmacología , Animales , Disponibilidad Biológica , Cricetinae , Cricetulus , AMP Cíclico/biosíntesis , Humanos , Técnicas In Vitro , Microsomas Hepáticos/metabolismo , Naftalenos/farmacocinética , Naftalenos/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Wistar , Relación Estructura-Actividad
4.
Eur J Pharmacol ; 484(2-3): 183-91, 2004 Jan 26.
Artículo en Inglés | MEDLINE | ID: mdl-14744602

RESUMEN

Interleukin-6 (IL-6) is markedly upregulated in the peripheral and central nervous systems following nerve injury; however, the functional effects of this are unclear. This study investigates the effect of peripheral interleukin-6 on nociceptive transmission in naive and neuropathic states. Using an in vitro rat skin-nerve preparation, 50 ng interleukin-6 inhibited responses of single nociceptive fibers to noxious heat. A 20-ng sample of interleukin-6 only inhibited heat responses in the presence of soluble interleukin-6 receptors. To examine in vivo effects of peripheral interleukin-6, extracellular recordings from dorsal horn neurons were made in anaesthetised naive, sham-operated and neuropathic (spinal nerve ligated) rats. Peripheral interleukin-6 (40-100 ng) markedly inhibited all naturally evoked neuronal responses in naive rats, yet only neuronal responses to heat in neuropathic rats. Behaviourally, intraplantar administration of interleukin-6 (0.01-1 microg) elicited ipsilateral thermal hypoalgesia in naive rats. Thus, interleukin-6 inhibits normal peripheral nociceptive transmission, yet such anti-nociceptive effects are attenuated following nerve injury in a modality-specific manner.


Asunto(s)
Potenciales de Acción/efectos de los fármacos , Interleucina-6/farmacología , Dimensión del Dolor/efectos de los fármacos , Nervios Espinales/efectos de los fármacos , Nervios Espinales/fisiopatología , Potenciales de Acción/fisiología , Vías Aferentes/efectos de los fármacos , Vías Aferentes/lesiones , Vías Aferentes/fisiología , Animales , Calor/efectos adversos , Masculino , Dimensión del Dolor/métodos , Traumatismos de los Nervios Periféricos , Nervios Periféricos/efectos de los fármacos , Nervios Periféricos/fisiología , Ratas , Ratas Sprague-Dawley , Nervios Espinales/lesiones , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología
5.
Brain Res ; 984(1-2): 54-62, 2003 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-12932839

RESUMEN

Interleukin-6 (IL-6) is a neuropoietic cytokine which is dramatically upregulated following peripheral nerve injury at the site of injury, in the dorsal root ganglion (DRG) and in the spinal cord. The functional effects of IL-6 in nociception in normal conditions and following nerve injury are unclear. Thus the aim of this study was to assess the effect of spinal IL-6 administration on nociceptive transmission in naive, sham-operated and neuropathic (spinal nerve ligation, SNL) rats using in vivo electrophysiology to elucidate the possible role of IL-6 in neuropathic pain. In anaesthetised rats, extracellular recordings were made from individual convergent dorsal horn neurones following electrical and natural (mechanical and thermal) stimulation of peripheral receptive fields. Exogenous spinal IL-6 (100-500 ng) had no significant effect on electrically evoked neuronal responses in naive rats. In contrast, following neuropathy, spinal IL-6 produced a dose-related inhibition of the electrically evoked C-fibre, initial C-fibre and measures of neuronal hyperexcitability (post discharge and wind-up). In addition, spinal IL-6 markedly inhibited mechanical neuronal responses in neuropathic rats. Higher doses of spinal IL-6 also inhibited, to a lesser degree, the initial C-fibre, post discharge and wind-up responses in sham-operated rats. These studies show that following nerve injury the actions of the cytokine alter so that spinal administration of IL-6 elicits anti-nociceptive effects not observed under normal conditions. Moreover, the inhibitory effects of IL-6 on C-fibre activity and neuronal hyperexcitability, suggest IL-6 to be a potential modulator of neuropathic pain.


Asunto(s)
Interleucina-6/fisiología , Inhibición Neural/fisiología , Dimensión del Dolor , Nervios Espinales/fisiología , Transmisión Sináptica/fisiología , Animales , Relación Dosis-Respuesta a Droga , Interleucina-6/farmacología , Masculino , Dimensión del Dolor/métodos , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Ratas , Ratas Sprague-Dawley , Médula Espinal/fisiología
6.
J Pharmacol Exp Ther ; 304(1): 56-62, 2003 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-12490575

RESUMEN

Vanilloid receptor type 1 (VR1) (TRPV1) is a ligand-gated ion channel expressed on sensory nerves that responds to noxious heat, protons, and chemical stimuli such as capsaicin. Herein, we have examined the activity of the VR1 antagonist capsazepine in models of inflammatory and neuropathic pain in the rat, mouse, and guinea pig. In naïve animals, subcutaneous administration of capsazepine (10-100 mg/kg s.c.) did not affect withdrawal thresholds to noxious thermal or mechanical stimuli. However, pretreatment with capsazepine prevented the development of mechanical hyperalgesia induced by intraplantar injection of capsaicin, with a similar potency in all three species. Capsazepine (up to 100 mg/kg s.c.) did not affect mechanical hyperalgesia in the Freund's complete adjuvant (FCA)-inflamed hind paw of the rat or mouse. Strikingly, capsazepine (3-30 mg/kg s.c.) produced up to 44% reversal of FCA-induced mechanical hyperalgesia in the guinea pig. Capsazepine also produced significant reversal of carageenan-induced thermal hyperalgesia in the guinea pig at 30 mg/kg s.c., but was ineffective in the rat. Similarly, in the partial sciatic nerve ligation model of neuropathic pain, capsazepine was surprisingly effective in the guinea pig, producing up to 80% reversal of mechanical hyperalgesia (1-30 mg/kg s.c.) but had no effect in the rat or mouse. These data show that VR1 antagonists have antihyperalgesic activity in animal models of chronic inflammatory and neuropathic pain, and illustrate species differences in the in vivo pharmacology of VR1 that correlate with differences in pharmacology previously seen in vitro.


Asunto(s)
Capsaicina/análogos & derivados , Capsaicina/farmacología , Hiperalgesia/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Receptores de Droga/antagonistas & inhibidores , Algoritmos , Animales , Anticonvulsivantes/farmacología , Carbamazepina/farmacología , Relación Dosis-Respuesta a Droga , Cobayas , Hiperalgesia/etiología , Hiperalgesia/patología , Inflamación/etiología , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedades del Sistema Nervioso Periférico/complicaciones , Enfermedades del Sistema Nervioso Periférico/patología , Ratas , Ratas Wistar , Nervio Ciático/patología
7.
Pain ; 100(3): 219-229, 2002 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-12467993

RESUMEN

Inoculation of syngeneic MRMT-1 mammary tumour cells into one tibia of female rats produced tumour growth within the bone associated with a reduction in bone mineral density (BMD) and bone mineral content (BMC), severe radiological signs of bone destruction, together with the development of behavioural mechanical allodynia and hyperalgesia. Histological and radiological examination showed that chronic treatment with the bisphosphonate, zoledronic acid (30 microg/kg, s.c.), for 19 days significantly inhibited tumour proliferation and preserved the cortical and trabecular bone structure. In addition, BMD and BMC were preserved and a dramatic reduction of tartrate resistant acid phosphatase-positive polykaryocytes (osteoclasts) was observed. In behavioural tests, chronic treatment with zoledronic acid but not the significantly less effective bisphosphonate, pamidronate, or the selective COX-2 inhibitor, celebrex, attenuated mechanical allodynia and hyperalgesia in the affected hind paw. Zoledronic acid also attenuated mechanical hyperalgesia associated with chronic peripheral neuropathy and inflammation in the rat. In contrast, pamidronate or clodronate did not have any anti-hyperalgesic effect on mechanical hyperalgesia in the neuropathic and inflammatory pain models. We conclude that zoledronic acid, in addition to, or independent from, its anti-metastatic and bone preserving therapeutic effects, is an anti-nociceptive agent in a rat model of metastatic cancer pain. This unique property of zoledronic acid amongst the bisphosphonate class of compounds could make this drug a preferred choice for the treatment of painful bone metastases in the clinic.


Asunto(s)
Neoplasias Óseas/complicaciones , Neoplasias Óseas/tratamiento farmacológico , Difosfonatos/administración & dosificación , Imidazoles/administración & dosificación , Dolor/tratamiento farmacológico , Dolor/etiología , Animales , Densidad Ósea/efectos de los fármacos , Neoplasias Óseas/diagnóstico por imagen , Neoplasias Óseas/patología , Ácido Clodrónico/administración & dosificación , Femenino , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/etiología , Hiperestesia/tratamiento farmacológico , Hiperestesia/etiología , Modelos Animales , Trasplante de Neoplasias , Variaciones Dependientes del Observador , Dimensión del Dolor/efectos de los fármacos , Umbral del Dolor/efectos de los fármacos , Pamidronato , Radiografía , Ratas , Ratas Sprague-Dawley , Valores de Referencia , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Tibia/efectos de los fármacos , Tibia/patología , Tibia/cirugía , Tacto/efectos de los fármacos , Resultado del Tratamiento , Ácido Zoledrónico
8.
Pain ; 98(3): 249-258, 2002 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-12127026

RESUMEN

Galanin is a 29-amino-acid neuropeptide that has been implicated in the processes of nociception. This study examines the effect of exogenous galanin on dorsal horn neurone activity in vivo in the spinal nerve ligation (SNL) model of neuropathic pain. SNL rats but not naive or sham-operated rats exhibited behaviour indicative of allodynia. In anaesthetized rats, extracellular recordings were made from individual convergent dorsal horn neurones following stimulation of peripheral receptive fields electrically or with natural (innocuous mechanical, noxious mechanical and noxious thermal) stimuli. Spinal administration of galanin (0.5-50 microg) caused a slight facilitation of the neuronal responses to natural and electrical stimuli in naive rats and up to a 65% inhibition of neuronal responses in sham-operated rats following 50 microg galanin. In contrast, there was a marked inhibition of up to 80% of responses to both natural and electrical stimuli in SNL rats following spinal galanin administration. These results suggest that following peripheral nerve injury, there is plasticity in the levels of galanin and/or its receptors at spinal cord level so that the effect of exogenous galanin favours inhibitory function.


Asunto(s)
Galanina/farmacología , Inhibición Neural/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Nervios Espinales/lesiones , Animales , Estimulación Eléctrica/métodos , Galanina/fisiología , Masculino , Inhibición Neural/fisiología , Plasticidad Neuronal/fisiología , Células del Asta Posterior/efectos de los fármacos , Células del Asta Posterior/fisiología , Ratas , Ratas Sprague-Dawley , Nervios Espinales/efectos de los fármacos , Nervios Espinales/fisiología
9.
Pain ; 87(3): 253-263, 2000 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-10963905

RESUMEN

The oral analgesic and anti-inflammatory activity of NK(1) antagonists with species preference for the human receptor were assessed in (1) the carrageenan-induced inflammatory hyperalgesia and (2) Freund's complete adjuvant (FCA)-induced extravasation in the knee joint models of the guinea-pig, respectively. Mechanical hyperalgesia was determined by measuring the withdrawal threshold to a noxious mechanical stimulus applied to the paw and thermal hyperalgesia as the withdrawal latency to a noxious thermal stimulus applied to the plantar surface. A concentration of 1.0% carrageenan (intraplantar) reduced mechanical thresholds from 124+/-5 to 63+/-3 g and thermal latencies from 19+/-0.4 to 4.7+/-0.9 s as determined 4 h after injection. The hyperalgesia persisted for over 24 h. The NK(1) receptor antagonists, SDZ NKT 343, RPR100893 and SR140333, reduced mechanical hyperalgesia by 68, 36 and 27% at a dose of 30 mg kg(-1) p.o., respectively. No further reduction was noted at higher doses (maximum 100 mg kg(-1) p.o.). The anti-hyperalgesic effect of SDZ NKT 343 and RPR100893 peaked at 3 h while SR140333 produced maximal reversal at 1 h after oral administration. D(30) values indicated significant differences between the potency of these compounds. SDZ NKT 343 was by far the most potent anti-hyperalgesic agent (D(30): 1.1 mg kg(-1)). The D(30) values for RPR100893 and SR140333 were estimated to be 17 and >100 mg kg(-1), respectively. In thermal hyperalgesia, SDZ NKT 343 produced a significantly weaker anti-hyperalgesic effect with a peak of 25% reversal. The D(30) value for SDZ NKT 343 was 3.89 mg kg(-1). For comparison, morphine inhibited the carrageenan-induced mechanical and thermal hyperalgesia with an ED(50) of 1.85 and 2.51 mg kg(-1) s.c., respectively. When tested up to 300 mg kg(-1) p.o., aspirin reduced carrageenan-induced mechanical and thermal hyperalgesia by 55.0 and 45.2%, respectively. In addition to the anti-hyperalgesic effects of NK(1) receptor antagonists, the effects of SDZ NKT 343 and RPR100893 on plasma protein extravasation were measured in the FCA-treated knee joint of the guinea-pig. SDZ NKT 343 reversed plasma protein extravasation 2 h after administration by 60% at the oral dose of 30 mg kg(-1). RPR100893 was significantly less effective with a maximum reversal of 30% at 100 mg kg(-1). In comparison, indomethacin produced a 50% reversal at a 10 mg kg(-1) dose. These experiments indicate that the carrageenan-induced hyperalgesia in the guinea-pig may be predictive of analgesic activity of NK(1) receptor antagonists in man. NK(1) receptor antagonists are active anti-hyperalgesic drugs in both mechanical and thermal hyperalgesia in the guinea-pig. In addition they inhibit plasma protein extravasation in the same species. The variability of in vivo potency and efficacy of the NK(1) receptor antagonists in the mechanical hyperalgesia model is difficult to interpret as all compounds are highly effective at blocking the NK(1) receptor in guinea-pig tissues. Amongst several possibilities, differences in pharmacokinetics may explain discrepancies.


Asunto(s)
Antiinflamatorios/uso terapéutico , Modelos Animales de Enfermedad , Hiperalgesia/tratamiento farmacológico , Naftalenos/uso terapéutico , Antagonistas del Receptor de Neuroquinina-1 , Prolina/análogos & derivados , Administración Oral , Animales , Carragenina , Femenino , Adyuvante de Freund , Cobayas , Humanos , Hiperalgesia/inducido químicamente , Indoles/uso terapéutico , Isoindoles , Masculino , Piperidinas/uso terapéutico , Prolina/uso terapéutico , Quinuclidinas/uso terapéutico
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA