title: A novel slow-inactivation-specific ion channel modulator attenuates neuropathic pain.
abstract: Voltage-gated ion channels are implicated in pain sensation and transmission signaling mechanisms within both peripheral nociceptors and the spinal cord. Genetic knockdown and knockout experiments have shown that specific channel isoforms, including Na(V)1.7 and Na(V)1.8 sodium channels and Ca(V)3.2 T-type calcium channels, play distinct pronociceptive roles. We have rationally designed and synthesized a novel small organic compound (Z123212) that modulates both recombinant and native sodium and calcium channel currents by selectively stabilizing channels in their slow-inactivated state. Slow inactivation of voltage-gated channels can function as a brake during periods of neuronal hyperexcitability, and Z123212 was found to reduce the excitability of both peripheral nociceptors and lamina I/II spinal cord neurons in a state-dependent manner. In vivo experiments demonstrate that oral administration of Z123212 is efficacious in reversing thermal hyperalgesia and tactile allodynia in the rat spinal nerve ligation model of neuropathic pain and also produces acute antinociception in the hot-plate test. At therapeutically relevant concentrations, Z123212 did not cause significant motor or cardiovascular adverse effects. Taken together, the state-dependent inhibition of sodium and calcium channels in both the peripheral and central pain signaling pathways may provide a synergistic mechanism toward the development of a novel class of pain therapeutics.
authors.affiliation: Zalicus Pharmaceuticals, 301-2389 Health Sciences Mall, Vancouver, BC, Canada V6T 1Z3 Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada T2N 4N1 Department of Pharmacology and Anesthesiology, University of Arizona, Tucson, AZ 85724, USA Michael Smith Laboratories, University of British Columbia, 2185 East Mall, Vancouver, BC, Canada V6T 1Z4.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Hildebrand
authors.forename: Paula L
authors.initials: PL
authors.lastname: Smith
authors.forename: Chris
authors.initials: C
authors.lastname: Bladen
authors.forename: Cyrus
authors.initials: C
authors.lastname: Eduljee
authors.forename: Jennifer Y
authors.initials: JY
authors.lastname: Xie
authors.forename: Lina
authors.initials: L
authors.lastname: Chen
authors.forename: Molly
authors.initials: M
authors.lastname: Fee-Maki
authors.forename: Clint J
authors.initials: CJ
authors.lastname: Doering
authors.forename: Janette
authors.initials: J
authors.lastname: Mezeyova
authors.forename: Yongbao
authors.initials: Y
authors.lastname: Zhu
authors.forename: Francesco
authors.initials: F
authors.lastname: Belardetti
authors.forename: Hassan
authors.initials: H
authors.lastname: Pajouhesh
authors.forename: David
authors.initials: D
authors.lastname: Parker
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Arneric
authors.forename: Manjeet
authors.initials: M
authors.lastname: Parmar
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Tringham
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Zamponi
authors.forename: Terrance P
authors.initials: TP
authors.lastname: Snutch
mesh_terms: D000083:Acetanilides / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D000179:Acrylates / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001703:Biophysics; D020747:Calcium Channels, T-Type / Q000235:genetics / Q000378:metabolism; D002461:Cell Line, Transformed; D004195:Disease Models, Animal; D004558:Electric Stimulation; D005727:Ganglia, Spinal / Q000473:pathology; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D066298:In Vitro Techniques; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D008297:Male; D049990:Membrane Transport Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D062556:NAV1.7 Voltage-Gated Sodium Channel; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009433:Neural Inhibition / Q000187:drug effects; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010147:Pain Measurement / Q000379:methods; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000473:pathology; D013127:Spinal Nerves / Q000473:pathology*; D013779:Tetrodotoxin / Q000494:pharmacology; D014162:Transfection / Q000379:methods
chemical_list: D000083:Acetanilides; D000179:Acrylates; C509958:Cacna1h protein, rat; D020747:Calcium Channels, T-Type; D007473:Ion Channels; D049990:Membrane Transport Modulators; D062556:NAV1.7 Voltage-Gated Sodium Channel; D062559:NAV1.8 Voltage-Gated Sodium Channel; D010879:Piperazines; C568317:SCN10A protein, human; C568319:Scn10a protein, rat; C503480:Scn9a protein, rat; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C559698:Z 123212; D013779:Tetrodotoxin; C023438:ethylacetylacrylate