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1.
Bioorg Med Chem Lett ; 20(15): 4359-63, 2010 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-20615696

RESUMEN

The transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is a non-selective cation channel that can be activated by a wide range of noxious stimuli, including capsaicin, acid, and heat. Blockade of TRPV1 activation by selective antagonists is under investigation in an attempt to identify novel agents for pain treatment. During pre-clinical development, the 1,8-naphthyridine 2 demonstrated unacceptably high levels of irreversible covalent binding. Replacement of the 1,8-naphthyridine core by a pyrido[2,3-b]pyrazine led to the discovery of compound 26 which was shown to have significantly lower potential for the formation of reactive metabolites. Compound 26 was characterized as an orally bioavailable TRPV1 antagonist with moderate brain penetration. In vivo, 26 significantly attenuated carrageenan-induced thermal hyperalgesia (CITH) and dose-dependently reduced complete Freund's adjuvant (CFA)-induced chronic inflammatory pain after oral administration.


Asunto(s)
Pirazinas/química , Canales Catiónicos TRPV/antagonistas & inhibidores , Administración Oral , Animales , Perros , Evaluación Preclínica de Medicamentos , Humanos , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Macaca mulatta , Microsomas Hepáticos/metabolismo , Naftiridinas/síntesis química , Naftiridinas/química , Dolor/tratamiento farmacológico , Pirazinas/farmacocinética , Pirazinas/uso terapéutico , Ratas , Canales Catiónicos TRPV/metabolismo
2.
J Med Chem ; 53(8): 3330-48, 2010 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-20307063

RESUMEN

The transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is a nonselective cation channel that can be activated by a wide range of noxious stimuli, including capsaicin, acid, and heat. Blockade of TRPV1 activation by selective antagonists is under investigation in an attempt to identify novel agents for pain treatment. The design and synthesis of a series of novel TRPV1 antagonists with a variety of different 6,6-heterocyclic cores is described, and an extensive evaluation of the pharmacological and pharmacokinetic properties of a number of these compounds is reported. For example, the 1,8-naphthyridine 52 was characterized as an orally bioavailable and brain penetrant TRPV1 antagonist. In vivo, 52 fully reversed carrageenan-induced thermal hyperalgesia (CITH) in rats and dose-dependently potently reduced complete Freund's adjuvant (CFA) induced chronic inflammatory pain after oral administration.


Asunto(s)
Analgésicos/síntesis química , Naftiridinas/síntesis química , Pirazinas/síntesis química , Piridinas/síntesis química , Pirimidinas/síntesis química , Canales Catiónicos TRPV/antagonistas & inhibidores , Analgésicos/química , Analgésicos/farmacología , Animales , Disponibilidad Biológica , Células COS , Capsaicina/farmacología , Chlorocebus aethiops , Calor , Humanos , Hiperalgesia/tratamiento farmacológico , Técnicas In Vitro , Inflamación/tratamiento farmacológico , Microsomas Hepáticos , Naftiridinas/química , Naftiridinas/farmacología , Dolor/tratamiento farmacológico , Pirazinas/química , Pirazinas/farmacología , Piridinas/química , Piridinas/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Quinazolinas/síntesis química , Quinazolinas/química , Quinazolinas/farmacología , Quinolinas/síntesis química , Quinolinas/química , Quinolinas/farmacología , Ratas , Relación Estructura-Actividad , Canales Catiónicos TRPV/agonistas
5.
Pain ; 98(1-2): 109-17, 2002 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-12098622

RESUMEN

The two-electrode voltage-clamp technique was used to evaluate the effect of protein kinase C (PKC) activation on ion current flow in Xenopus laevis oocytes injected with cRNA coding for the human vanilloid receptor (VR1). In the presence of 30 nM phorbol-12,13-dibutyrate (PDBu), current evoked by an effective concentration (EC(30)) of capsaicin (CAP) was potentiated by 638+/-117% (n=8). PDBu exhibited an EC(50) of about 17+/-3 nM for this effect (n=8). Potentiation was not observed when VR1 expressing oocytes were exposed to both 30 nM PDBu and 1 microM staurosporine. In the presence of 300 nM PDBu, the EC(50) for CAP shifted from 899+/-78 to 139+/-2 1 nM (n=11 and 5, respectively). In the presence of 30 nM PDBu, the maximal current amplitude evoked by application of CAP increased by 86+/-21% (n=10), in a staurosporine sensitive manner. Application of 1 microM PDBu alone elicited a capsazepine sensitive current within 3 min of exposure. This effect was observed in the absence of previous exposure of the oocyte to CAP and was abolished in the presence of 1 microM staurosporine. No current was elicited during a 10 min application of 300 nM PDBu, the longest interval assessed. Prior to 30 nM PDBu exposure, no current was evoked at temperature ramps from room temperature (22-23 degrees C) up to 37 degrees C at pH 6.8, 7.0, or 7.4. Following PDBu treatment, VR1 mediated current was evoked at 26 degrees C at pH 7.0. Likewise, following 30 nM PDBu treatment, current was evoked by application of pH 6.8 alone and a further increase in current amplitude was evoked by heat at 24 degrees C in a staurosporine sensitive manner. These data provide direct evidence that PKC activation can increase VR1 current evoked by candidate physiological activators, pH and heat. This observation provides an empirical foundation for explaining some types of inflammatory pain in terms of PKC activation, small decreases in tissue pH levels, and small increases in skin temperature, all of which can accompany inflammatory conditions.


Asunto(s)
Capsaicina/farmacología , Hidrógeno/metabolismo , Proteína Quinasa C/metabolismo , Receptores de Droga/efectos de los fármacos , Temperatura , Animales , Electrofisiología , Activación Enzimática/fisiología , Femenino , Humanos , Concentración de Iones de Hidrógeno , Oocitos , Receptores de Droga/fisiología , Xenopus laevis
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