title: Effects of a new potent analog of tocainide on hNav1.7 sodium channels and in vivo neuropathic pain models.
abstract: The role of voltage-gated sodium channels in the transmission of neuropathic pain is well recognized. For instance, genetic evidence recently indicate that the human Nav1.7 sodium channel subtype plays a crucial role in the ability to perceive pain sensation and may represent an important target for analgesic/anti-hyperalgesic drugs. In this study a newly synthesized tocainide congener, named NeP1, was tested in vitro on recombinant hNav1.4 and hNav1.7 channels using patch-clamp technique and, in vivo, in two rat models of persistent neuropathic pain obtained either by chronic constriction injury of the sciatic nerve or by oxaliplatin treatment. NeP1 efficiently blocked hNav1.4 and hNav1.7 channels in a dose- and use-dependent manner, being by far more potent than tocainide. Importantly, the new compound displayed a remarkable use-dependent effect, which likely resulted from a very high affinity for inactivated compared to closed channels. In both models of neuropathic pain, NeP1 was greatly more potent than tocainide in reverting the reduction of pain threshold in vivo. In oxaliplatin-treated rats, NeP1 even produced greater and more durable anti-hyperalgesia than the reference drug tramadol. In addition, in vivo and in vitro studies suggest a better toxicological and pharmacokinetic profile for NeP1 compared to tocainide. Overall, these results indicate NeP1 as a new promising lead compound for further development in the treatment of chronic pain of neuropathic origin.
authors.affiliation: Department of Preclinical and Clinical Pharmacology, Faculty of Pharmacy, University of Florence, Florence, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Ghelardini
authors.forename: J-F
authors.initials: JF
authors.lastname: Desaphy
authors.forename: M
authors.initials: M
authors.lastname: Muraglia
authors.forename: F
authors.initials: F
authors.lastname: Corbo
authors.forename: R
authors.initials: R
authors.lastname: Matucci
authors.forename: A
authors.initials: A
authors.lastname: Dipalma
authors.forename: C
authors.initials: C
authors.lastname: Bertucci
authors.forename: M
authors.initials: M
authors.lastname: Pistolozzi
authors.forename: M
authors.initials: M
authors.lastname: Nesi
authors.forename: M
authors.initials: M
authors.lastname: Norcini
authors.forename: C
authors.initials: C
authors.lastname: Franchini
authors.forename: D Conte
authors.initials: DC
authors.lastname: Camerino
mesh_terms: D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy; D008297:Male; D009124:Muscle Proteins / Q000037:antagonists & inhibitors; D062553:NAV1.4 Voltage-Gated Sodium Channel; D062556:NAV1.7 Voltage-Gated Sodium Channel; D010146:Pain / Q000188:drug therapy*; D018408:Patch-Clamp Techniques; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D012709:Serum Albumin / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D015222:Sodium Channels / Q000502:physiology*; D016677:Tocainide / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C553457:1-benzyl-N-(2,6-dimethylphenyl)-3-pyrrolidine carboxamide; D000700:Analgesics; D009124:Muscle Proteins; D062553:NAV1.4 Voltage-Gated Sodium Channel; D062556:NAV1.7 Voltage-Gated Sodium Channel; C106251:SCN4A protein, human; C486866:SCN9A protein, human; D012709:Serum Albumin; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D016677:Tocainide