RESUMEN
Here we report on a novel fluorescent analog of phenytoin as a potential inhibitor of neuropathic pain with potential use as an imaging agent. Compound 2 incorporated a heptyl side chain and dansyl moiety onto the parent compound phenytoin and produced greater displacement of BTX from sodium channels and greater functional blockade with greatly reduced toxicity. Compound 2 reduced mechano-allodynia in a rat model of neuropathic pain and was visualized ex vivo in sensory neuron axons with two-photon microscopy. These results suggest a promising strategy for developing novel sodium channel inhibitors with imaging capabilities.
Asunto(s)
Fluorescencia , Colorantes Fluorescentes/farmacología , Neuralgia/tratamiento farmacológico , Fenitoína/farmacología , Bloqueadores de los Canales de Sodio/farmacología , Animales , Modelos Animales de Enfermedad , Diseño de Fármacos , Femenino , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/química , Modelos Moleculares , Estructura Molecular , Fenitoína/síntesis química , Fenitoína/química , Ratas , Ratas Sprague-Dawley , Bloqueadores de los Canales de Sodio/síntesis química , Bloqueadores de los Canales de Sodio/química , Relación Estructura-ActividadRESUMEN
Hermitamides A and B are lipopeptides isolated from a Papau New Guinea collection of the marine cyanobacterium Lyngbya majuscula. We hypothesized that the hermitamides are ligands for the human voltage-gated sodium channel (hNa(V)) based on their structural similarity to the jamaicamides. Herein, we describe the nonracemic total synthesis of hermitamides A and B and their epimers. We report the ability of the hermitamides to displace [(3)H]-BTX at 10 µM more potently than phenytoin, a clinically used sodium channel blocker. We also present a potential binding mode for (S)-hermitamide B in the BTX-binding site and electrophysiology showing that these compounds are potent blockers of the hNav1.2 voltage-gated sodium channel.
Asunto(s)
Amidas/farmacología , Indoles/farmacología , Fenetilaminas/farmacología , Bloqueadores de los Canales de Sodio/farmacología , Canales de Sodio/metabolismo , Amidas/síntesis química , Amidas/química , Línea Celular , Humanos , Indoles/síntesis química , Indoles/química , Modelos Moleculares , Conformación Molecular , Fenetilaminas/síntesis química , Fenetilaminas/química , Bloqueadores de los Canales de Sodio/síntesis química , Bloqueadores de los Canales de Sodio/química , Canales de Sodio/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Alzheimer's disease causes a progressive dementia that currently affects over 35 million individuals worldwide and is expected to affect 115 million by 2050 (ref. 1). There are no cures or disease-modifying therapies, and this may be due to our inability to detect the disease before it has progressed to produce evident memory loss and functional decline. Biomarkers of preclinical disease will be critical to the development of disease-modifying or even preventative therapies. Unfortunately, current biomarkers for early disease, including cerebrospinal fluid tau and amyloid-ß levels, structural and functional magnetic resonance imaging and the recent use of brain amyloid imaging or inflammaging, are limited because they are either invasive, time-consuming or expensive. Blood-based biomarkers may be a more attractive option, but none can currently detect preclinical Alzheimer's disease with the required sensitivity and specificity. Herein, we describe our lipidomic approach to detecting preclinical Alzheimer's disease in a group of cognitively normal older adults. We discovered and validated a set of ten lipids from peripheral blood that predicted phenoconversion to either amnestic mild cognitive impairment or Alzheimer's disease within a 2-3 year timeframe with over 90% accuracy. This biomarker panel, reflecting cell membrane integrity, may be sensitive to early neurodegeneration of preclinical Alzheimer's disease.