RESUMEN
3-Aryl-indole and 3-aryl-indazole derivatives were identified as potent and selective Nav1.7 inhibitors. Compound 29 was shown to be efficacious in the mouse formalin assay and also reduced complete Freund's adjuvant (CFA)-induced thermal hyperalgesia and chronic constriction injury (CCI) induced cold allodynia and models of inflammatory and neuropathic pain, respectively, following intraperitoneal (IP) doses of 30 mg/kg. The observed efficacy could be correlated with the mouse dorsal root ganglion exposure and NaV1.7 potency associated with 29.
Asunto(s)
Indazoles/química , Indoles/química , Canal de Sodio Activado por Voltaje NAV1.7/química , Neuralgia/tratamiento farmacológico , Sulfonamidas/química , Bloqueadores del Canal de Sodio Activado por Voltaje/uso terapéutico , Animales , Evaluación Preclínica de Medicamentos , Células HEK293 , Semivida , Humanos , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/patología , Masculino , Ratones , Canal de Sodio Activado por Voltaje NAV1.7/metabolismo , Neuralgia/patología , Técnicas de Placa-Clamp , Relación Estructura-Actividad , Sulfonamidas/metabolismo , Sulfonamidas/uso terapéutico , Bloqueadores del Canal de Sodio Activado por Voltaje/química , Bloqueadores del Canal de Sodio Activado por Voltaje/metabolismoRESUMEN
A class of bisarylimidazole derivatives are identified as potent inhibitors of the enzyme fatty acid amide hydrolase (FAAH). Compound 17 (IC(50)=2 nM) dose-dependently (0.1-10mg/kg, iv) potentiates the effects of exogenous anandamide (1 mg/kg, iv) in a rat thermal escape test (Hargreaves test), and shows robust antinociceptive activity in animal models of persistent (formalin test) and neuropathic (Chung model) pain. Compound 17 (20 mg/kg, iv) demonstrates activity in the formalin test that is comparable to morphine (3mg/kg, iv), and is dose-dependently inhibited by the CB1 antagonist SR141716A. In the Chung model, compound 17 shows antineuropathic effects similar to high-dose (100 mg/kg) gabapentin. FAAH inhibition shows potential utility for the clinical treatment of persistent and neuropathic pain.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Analgésicos/farmacología , Inhibidores Enzimáticos/farmacología , Imidazoles/farmacología , Dimensión del Dolor/efectos de los fármacos , Aminas/farmacología , Analgésicos/administración & dosificación , Animales , Ácidos Ciclohexanocarboxílicos/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Gabapentina , Humanos , Imidazoles/química , Ratones , Ratones Noqueados , Morfina/farmacología , Dimensión del Dolor/métodos , Piperidinas/antagonistas & inhibidores , Piperidinas/metabolismo , Pirazoles/antagonistas & inhibidores , Pirazoles/metabolismo , Ratas , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptor Cannabinoide CB1/metabolismo , Rimonabant , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
Recent findings suggest that Alzheimer's dementia may be mediated by soluble beta amyloid (Abeta) more than the deposits of aggregated, insoluble Abeta, and vulnerability to cognitive deficits after scopolamine challenge may help identify AD even in patients that are still pre-symptomatic. The objectives of the present experiments were to determine if vulnerability to cognitive deficits after scopolamine challenge is related to levels of soluble Abeta, and if levels of soluble Abeta are more closely related to cognitive deficits than levels of insoluble Abeta, even in aged, transgenic mice, after they have developed very high levels of insoluble Abeta. Aged F-344 rats and young mice over-expressing the Swedish mutation in the human amyloid precursor protein (APPsw; Tg2576+) had elevated levels of soluble Abeta, and were more vulnerable to scopolamine challenge in the Morris water maze (MWM), relative to young rats and Tg2576- mice; but, among individual animals, higher levels of soluble Abeta were not correlated with vulnerability to scopolamine. On the other hand, in aged Tg2576+ mice, cognitive deficits were related to levels of soluble Abeta, not insoluble Abeta, despite the fact that the levels of insoluble Abeta were thousands of times higher than the levels of soluble Abeta. The results of the present experiments suggest that vulnerability to cognitive deficits after scopolamine challenge is not related to elevated levels of soluble Abeta, but that high levels of soluble Abeta are more closely correlated with cognitive deficits than the amount insoluble Abeta, even after large amounts of aggregated, insoluble Abeta have been deposited.