title: 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.
authors.affiliation: Lohocla Research Corporation, Colorado Bioscience Building, 12635 East Montview Blvd., Suite 128, Aurora, CO 80045, USA; Department of Pharmaceutical Sciences, Skaggs School of Pharmacy & Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Campus Box: C238 12850, E. Montview Blvd., Aurora, CO 80045, USA. Electronic address: boris.tabakoff@Lohocla.com.
authors.forename: Boris
authors.initials: B
authors.lastname: Tabakoff
authors.affiliation: Lohocla Research Corporation, Colorado Bioscience Building, 12635 East Montview Blvd., Suite 128, Aurora, CO 80045, USA. Electronic address: wenhua.ren@ucdenver.edu.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Ren
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy & Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Campus Box: C238 12850, E. Montview Blvd., Aurora, CO 80045, USA. Electronic address: lauren.vanderlinden@ucdenver.edu.
authors.forename: Lauren
authors.initials: L
authors.lastname: Vanderlinden
authors.affiliation: Lohocla Research Corporation, Colorado Bioscience Building, 12635 East Montview Blvd., Suite 128, Aurora, CO 80045, USA. Electronic address: LDSnell56@gmail.com.
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: Snell
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy & Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Campus Box: C238 12850, E. Montview Blvd., Aurora, CO 80045, USA. Electronic address: chris.matheson@ucdenver.edu.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Matheson
authors.affiliation: Department of Pharmacology, University of Colorado Anschutz Medical Campus, 12800 E. 19 Ave., Aurora, CO 80045 USA. Electronic address: zwang@Howard.edu.
authors.forename: Ze-Jun
authors.initials: ZJ
authors.lastname: Wang
authors.affiliation: Department of Physiology & Biophysics, University of Colorado Anschutz Medical Campus, 12800 E. 19th Ave., Aurora, CO 80045, USA. Electronic address: rock.levinson@ucdenver.edu.
authors.forename: Rock
authors.initials: R
authors.lastname: Levinson
authors.affiliation: Department of Neurosciences and Department of Psychiatry, Medical University of South Carolina, 171 Ashley Ave., Charleston, SC 29425, USA. Electronic address: corigan3@aim.com.
authors.forename: C Thetford
authors.initials: CT
authors.lastname: Smothers
authors.affiliation: Department of Neurosciences and Department of Psychiatry, Medical University of South Carolina, 171 Ashley Ave., Charleston, SC 29425, USA. Electronic address: woodward@musc.edu.
authors.forename: John J
authors.initials: JJ
authors.lastname: Woodward
authors.affiliation: Clinical and Biological Research Unit, NIAAA, 12420 Parklawn Dr., MSC 8115, Bethesda, MD 20892-8115, USA. Electronic address: honseymk@hotmail.com.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Honse
authors.affiliation: Clinical and Biological Research Unit, NIAAA, 12420 Parklawn Dr., MSC 8115, Bethesda, MD 20892-8115, USA. Electronic address: lovindav@mail.nih.gov.
authors.forename: David
authors.initials: D
authors.lastname: Lovinger
authors.affiliation: Neurosolutions Ltd., Coventry CV4 7ZS, United Kingdom. Electronic address: tony.rush@metrionbiosciences.com.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Rush
authors.affiliation: Department of Pharmacology, University of Colorado Anschutz Medical Campus, 12800 E. 19 Ave., Aurora, CO 80045 USA. Electronic address: william.sather@ucdenver.edu.
authors.forename: William A
authors.initials: WA
authors.lastname: Sather
authors.affiliation: UCCC Pharmacology Shared Resource, Colorado State University, Veterinary Teaching Hospital, A CC246, 300 West Drake Road, Fort Collins, CO 80023, USA. Electronic address: daniel.gustafson@ColoState.edu.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Gustafson
authors.affiliation: Department of Pharmacology, University of Colorado Anschutz Medical Campus, 12800 E. 19 Ave., Aurora, CO 80045 USA. Electronic address: paula.hoffman@ucdenver.edu.
authors.forename: Paula L
authors.initials: PL
authors.lastname: Hoffman
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000097:blood / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells; D002908:Chronic Disease; D006224:Cricetinae; D003412:Cricetulus; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D058990:Molecular Targeted Therapy; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D020033:Protein Isoforms / Q000378:metabolism; D011804:Quinolines / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000097:blood / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; C403081:N,N-(diphenyl)-4-ureido-5,7-dichloro-2-carboxyquinoline; D010671:Phenylurea Compounds; D020033:Protein Isoforms; D011804:Quinolines; D016194:Receptors, N-Methyl-D-Aspartate; D026941:Sodium Channel Blockers; D061566:Voltage-Gated Sodium Channels
keywords: Chronic pain; GluN2B; NMDA; Na(v)1.7; Na(v)1.8; Substituted aminoquinoline