A Disubstituted Succinamide Is a Potent Sodium Channel Blocker with Efficacy in a Rat Pain Model

• Published in: Biochemistry (Easton) 2004-08, Vol.43 (30), p.9866-9876
• Main Authors: Priest, Birgit T, Garcia, Maria L, Middleton, Richard E, Brochu, Richard M, Clark, Samantha, Dai, Ge, Dick, Ivy E, Felix, John P, Liu, Chou J, Reiseter, Brita S, Schmalhofer, William A, Shao, Pengcheng P, Tang, Yui S, Chou, Margaret Z, Kohler, Martin G, Smith, McHardy M, Warren, Vivien A, Williams, Brande S, Cohen, Charles J, Martin, William J, Meinke, Peter T, Parsons, William H, Wafford, Keith A, Kaczorowski, Gregory J
• Format: Article
• Language: English
• Subjects: Amides - chemical synthesis; Amides - metabolism; Amides - therapeutic use; Analgesics - chemical synthesis; Analgesics - metabolism; Analgesics - therapeutic use; Animals; Binding Sites; Biphenyl Compounds - chemical synthesis; Biphenyl Compounds - metabolism; Biphenyl Compounds - therapeutic use; Brain - metabolism; Cell Line; Disease Models, Animal; Formaldehyde - administration & dosage; Ganglia, Spinal - drug effects; Ganglia, Spinal - metabolism; Humans; Mice; Muscle Proteins - biosynthesis; Muscle Proteins - genetics; Muscle Proteins - metabolism; NAV1.2 Voltage-Gated Sodium Channel; NAV1.5 Voltage-Gated Sodium Channel; NAV1.7 Voltage-Gated Sodium Channel; Nerve Tissue Proteins - antagonists & inhibitors; Nerve Tissue Proteins - biosynthesis; Nerve Tissue Proteins - genetics; Pain Measurement - drug effects; Patch-Clamp Techniques; Rats; Recombinant Proteins - antagonists & inhibitors; Recombinant Proteins - biosynthesis; Sodium Channel Blockers - chemical synthesis; Sodium Channel Blockers - metabolism; Sodium Channel Blockers - therapeutic use; Sodium Channels - biosynthesis; Sodium Channels - genetics; Sodium Channels - metabolism; Succinates; Synaptosomes - metabolism; Tetrodotoxin - antagonists & inhibitors; Tetrodotoxin - chemistry
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi0493259

Sodium channel blockers are used clinically to treat a number of neuropathic pain conditions, but more potent and selective agents should improve on the therapeutic index of currently used drugs. In a high-throughput functional assay, a novel sodium channel (NaV) blocker, N-{[2‘-(aminosulfonyl)biphenyl-4-yl]methyl}-N‘-(2,2‘-bithien-5-ylmethyl)succinamide (BPBTS), was discovered. BPBTS is 2 orders of magnitude more potent than anticonvulsant and antiarrhythmic sodium channel blockers currently used to treat neuropathic pain. Resembling block by these agents, block of NaV1.2, NaV1.5, and NaV1.7 by BPBTS was found to be voltage- and use-dependent. BPBTS appeared to bind preferentially to open and inactivated states and caused a dose-dependent hyperpolarizing shift in the steady-state availability curves for all sodium channel subtypes tested. The affinity of BPBTS for the resting and inactivated states of NaV1.2 was 1.2 and 0.14 μM, respectively. BPBTS blocked NaV1.7 and NaV1.2 with similar potency, whereas block of NaV1.5 was slightly more potent. The slow tetrodotoxin-resistant Na+ current in small-diameter DRG neurons was also potently blocked by BPBTS. [3H]BPBTS bound with high affinity to a single class of sites present in rat brain synaptosomal membranes (K d = 6.1 nM), and in membranes derived from HEK cells stably expressing NaV1.5 (K d = 0.9 nM). BPBTS dose-dependently attenuated nociceptive behavior in the formalin test, a rat model of tonic pain. On the basis of these findings, BPBTS represents a structurally novel and potent sodium channel blocker that may be used as a template for the development of analgesic agents.