A novel substituted aminoquinoline selectively targets voltage-sensitive sodium channel isoforms and NMDA receptor subtypes and alleviates chronic inflammatory and neuropathic pain

Abstract

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.

Controlling the “Opioid Epidemic”: A Novel Chemical Entity (NCE) to Reduce or Supplant Opiate Use for Chronic Pain

“…The effect of Kindolor to ameliorate pain in five animal models is described in our publication [ 56 ], and was provided as preliminary data on efficacy in our grant application. In addition we showed in our preliminary data a synergistic effect of Kindolor in combination with morphine or aspirin to reduce inflammatory pain (caused by Complete Freund’s Adjuvant) or diabetic neuropathic pain (caused by streptozotocin treatment), respectively.…”

“…The illustrated actions of Kindolor are extrapolated from its measured actions on receptors and ion channels in model systems and demonstrations in the literature on the participation of the receptors/channels in generation and conduction of pain formation in sensory systems. It remains to be directly demonstrated that the antihyperalgesic actions of Kindolor are specifically mediated by the illustrated events [ 56 ].…”

“…The glutamate activates NMDA receptors on the neighboring (juxtaposed) sensory neuron cell body and instigates depolarization and conduction of signal to the spinal cord [ 92 ]. Kindolor, by inhibiting the NMDA receptor on cell bodies of the sensory neurons prevents the amplification of the signal mediated by the sandwich synapses [ 56 , 69 , 90 – 92 ].…”

“…The “non-selective” sodium channel blockers, mentioned above, have the opposite order of potency [ 54 ]. Kindolor, unlike the “non- selective” agents [ 55 ], has little, or no, effect on Nav 1.5, a channel with intermediate sensitivity to tetrodotoxin [ 56 ]. Kindolor has no effect on acute pain as witnessed in the early stage of the formalin test in mice (i.e., it is not an analgesic), but reduces the later (chronic) pain to pre-formalin injection levels (acts as an antihyperalgesic) [ 4 , 7 ].…”

β-Elemene alleviates bone cancer-related pain in rats by modulating N-methyl-D-aspartate receptor 2B subunit

“…N-methyl-D-aspartate (NMDA) receptors are relevant to chronic neuropathic pain, injury-induced pain behaviour and persistent pain of spinal lamina II neurons [10][11][12][13]. The NMDA receptor 2B subunit (N R 2B) shows a relatively restricted distribution in pathways of nociceptive transmission [14].…”