A novel substituted aminoquinoline selectively targets voltage-sensitive sodium channel isoforms and NMDA receptor subtypes and alleviates chronic inflammatory and neuropathic pain
Autor: | David M. Lovinger, Rock Levinson, Boris Tabakoff, Yumiko Honse, John J. Woodward, Anthony M. Rush, Paula L. Hoffman, Lawrence D. Snell, William A. Sather, Daniel L. Gustafson, Lauren A. Vanderlinden, Ze-Jun Wang, Wenhua Ren, Christopher J. Matheson, C. Thetford Smothers |
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Jazyk: | angličtina |
Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Male Central nervous system Anti-Inflammatory Agents CHO Cells Voltage-Gated Sodium Channels Pharmacology Receptors N-Methyl-D-Aspartate Article Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Cricetulus Cricetinae medicine Animals Humans Protein Isoforms Molecular Targeted Therapy Receptor Sensitization Inflammation Chemistry Sodium channel Phenylurea Compounds Chronic pain Brain medicine.disease Rats 030104 developmental biology medicine.anatomical_structure HEK293 Cells Hyperalgesia Neuropathic pain Chronic Disease Quinolines NMDA receptor Neuralgia medicine.symptom Neuroscience 030217 neurology & neurosurgery Sodium Channel Blockers |
Popis: | Recent understanding of the systems that mediate complex disease states, has generated a search for molecules that simultaneously modulate more than one component of a pathologic pathway. Chronic pain syndromes are etiologically connected to functional changes (sensitization) in both peripheral sensory neurons and in the central nervous system (CNS). These functional changes involve modifications of a significant number of components of signal generating, signal transducing and signal propagating pathways. Our analysis of disease-related changes which take place in sensory neurons during sensitization led to the design of a molecule that would simultaneously inhibit peripheral NMDA receptors and voltage sensitive sodium channels. In the current report, we detail the selectivity of N,N-(diphenyl)-4-ureido-5,7-dichloro-2-carboxy-quinoline (DCUKA) for action at NMDA receptors composed of different subunit combinations and voltage sensitive sodium channels having different α subunits. We show that DCUKA is restricted to the periphery after oral administration, and that circulating blood levels are compatible with its necessary concentrations for effects at the peripheral cognate receptors/channels that were assayed in vitro. Our results demonstrate that DCUKA, at concentrations circulating in the blood after oral administration, can modulate systems which are upregulated during peripheral sensitization, and are important for generating and conducting pain information to the CNS. Furthermore, we demonstrate that DCUKA ameliorates the hyperalgesia of chronic pain without affecting normal pain responses in neuropathic and inflammation-induced chronic pain models. |
Databáze: | OpenAIRE |
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