title: Characterization of a new class of potent inhibitors of the voltage-gated sodium channel Nav1.7.
abstract: Voltage-gated sodium channels (Nav1) transmit pain signals from peripheral nociceptive neurons, and blockers of these channels have been shown to ameliorate a number of pain conditions. Because these drugs can have adverse effects that limit their efficacy, more potent and selective Nav1 inhibitors are being pursued. Recent human genetic data have provided strong evidence for the involvement of the peripheral nerve sodium channel subtype, Nav1.7, in the signaling of nociceptive information, highlighting the importance of identifying selective Nav1.7 blockers for the treatment of chronic pain. Using a high-throughput functional assay, novel Nav1.7 blockers, namely, the 1-benzazepin-2-one series, have recently been identified. Further characterization of these agents indicates that, in addition to high-affinity inhibition of Nav1.7 channels, selectivity against the Nav1.5 and Nav1.8 subtypes can also be achieved within this structural class. The most potent, nonselective member of this class of Nav1.7 blockers has been radiolabeled with tritium. [3H]BNZA binds with high affinity to rat brain synaptosomal membranes (Kd = 1.5 nM) and to membranes prepared from HEK293 cells stably transfected with hNav1.5 (Kd = 0.97 nM). In addition, and for the first time, high-affinity binding of a radioligand to hNav1.7 channels (Kd = 1.6 nM) was achieved with [3H]BNZA, providing an additional means for identifying selective Nav1.7 channel inhibitors. Taken together, these data suggest that members of the novel 1-benzazepin-2-one structural class of Nav1 blockers can display selectivity toward the peripheral nerve Nav1.7 channel subtype, and with appropriate pharmacokinetic and drug metabolism properties, these compounds could be developed as analgesic agents.
authors.affiliation: Department of Ion Channels, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, USA.
authors.forename: Brande S
authors.initials: BS
authors.lastname: Williams
authors.forename: John P
authors.initials: JP
authors.lastname: Felix
authors.forename: Birgit T
authors.initials: BT
authors.lastname: Priest
authors.forename: Richard M
authors.initials: RM
authors.lastname: Brochu
authors.forename: Kefei
authors.initials: K
authors.lastname: Dai
authors.forename: Scott B
authors.initials: SB
authors.lastname: Hoyt
authors.forename: Clare
authors.initials: C
authors.lastname: London
authors.forename: Yui S
authors.initials: YS
authors.lastname: Tang
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Duffy
authors.forename: William H
authors.initials: WH
authors.lastname: Parsons
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Kaczorowski
authors.forename: Maria L
authors.initials: ML
authors.lastname: Garcia
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004594:Electrophysiology; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D015394:Molecular Structure; D062556:NAV1.7 Voltage-Gated Sodium Channel; D062559:NAV1.8 Voltage-Gated Sodium Channel; D011869:Radioligand Assay; D051381:Rats; D026941:Sodium Channel Blockers / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D013574:Synaptosomes / Q000378:metabolism
chemical_list: D001552:Benzazepines; D062556:NAV1.7 Voltage-Gated Sodium Channel; D062559:NAV1.8 Voltage-Gated Sodium Channel; C568317:SCN10A protein, human; C486866:SCN9A protein, human; C568319:Scn10a protein, rat; D026941:Sodium Channel Blockers; D015222:Sodium Channels