A disubstituted succinamide is a potent sodium channel blocker with efficacy in a rat pain model.
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 (Na(V)) 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 Na(V)1.2, Na(V)1.5, and Na(V)1.7 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 Na(V)1.2 was 1.2 and 0.14 microM, respectively. BPBTS blocked Na(V)1.7 and Na(V)1.2 with similar potency, whereas block of Na(V)1.5 was slightly more potent. The slow tetrodotoxin-resistant Na(+) current in small-diameter DRG neurons was also potently blocked by BPBTS. [(3)H]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 Na(V)1.5 (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.
Department of Ion Channels, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
Birgit T
BT
Priest
Maria L
ML
Garcia
Richard E
RE
Middleton
Richard M
RM
Brochu
Samantha
S
Clark
Ge
G
Dai
Ivy E
IE
Dick
John P
JP
Felix
Chou J
CJ
Liu
Brita S
BS
Reiseter
William A
WA
Schmalhofer
Pengcheng P
PP
Shao
Yui S
YS
Tang
Margaret Z
MZ
Chou
Martin G
MG
Kohler
McHardy M
MM
Smith
Vivien A
VA
Warren
Brande S
BS
Williams
Charles J
CJ
Cohen
William J
WJ
Martin
Peter T
PT
Meinke
William H
WH
Parsons
Keith A
KA
Wafford
Gregory J
GJ
Kaczorowski
D000577:Amides / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use*; D000700:Analgesics / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use; D000818:Animals; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use*; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D005557:Formaldehyde / Q000008:administration & dosage; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D009124:Muscle Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D062551:NAV1.2 Voltage-Gated Sodium Channel; D062554:NAV1.5 Voltage-Gated Sodium Channel; D062556:NAV1.7 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D010147:Pain Measurement / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D026941:Sodium Channel Blockers / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use*; D015222:Sodium Channels / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D013386:Succinates; D013574:Synaptosomes / Q000378:metabolism; D013779:Tetrodotoxin / Q000037:antagonists & inhibitors / Q000737:chemistry
D000577:Amides; D000700:Analgesics; D001713:Biphenyl Compounds; D009124:Muscle Proteins; C490513:N-((2'-(aminosulfonyl)biphenyl-4-yl)methyl)-N'-(2,2'-bithien-5-ylmethyl)succinamide; D062551:NAV1.2 Voltage-Gated Sodium Channel; D062554:NAV1.5 Voltage-Gated Sodium Channel; D062556:NAV1.7 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; C568251:SCN2A protein, human; C568320:SCN5A protein, human; C568253:Scn2A protein, rat; C000654500:Scn2a protein, mouse; C568321:Scn5a protein, mouse; C568322:Scn5a protein, rat; C503480:Scn9a protein, rat; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013386:Succinates; D005557:Formaldehyde; D013779:Tetrodotoxin; C011116:succinamide