Characterization of a New Class of Potent Inhibitors of the Voltage-Gated Sodium Channel Nav1.7

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• 作者：Brande S. Williams ; John P. Felix ; Birgit T. Priest ; Richard M. Brochu ; Kefei Dai ; Scott B. Hoyt ; Clare London ; Yui S. Tang ; Joseph L. Duffy ; William H. Parsons ; Gregory J. Kaczorowski ; Maria L. Garcia
• 刊名：Biochemistry
• 出版年：2007
• 出版时间：December 18, 2007
• 年：2007
• 卷：46
• 期：50
• 页码：14693 - 14703
• 全文大小：301K
• 年卷期：v.46,no.50(December 18, 2007)
• ISSN：1520-4995

文摘

Voltage-gated sodium channels (Nav1) transmit pain signals from peripheral nociceptiveneurons, 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 Nav1inhibitors are being pursued. Recent human genetic data have provided strong evidence for the involvementof 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 beachieved within this structural class. The most potent, nonselective member of this class of Nav1.7 blockershas been radiolabeled with tritium. [³H]BNZA binds with high affinity to rat brain synaptosomal membranes(K_d = 1.5 nM) and to membranes prepared from HEK293 cells stably transfected with hNav1.5 (K_d =0.97 nM). In addition, and for the first time, high-affinity binding of a radioligand to hNav1.7 channels(K_d = 1.6 nM) was achieved with [³H]BNZA, providing an additional means for identifying selectiveNav1.7 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 channelsubtype, and with appropriate pharmacokinetic and drug metabolism properties, these compounds couldbe developed as analgesic agents.