A disubstituted succinamide is a potent sodium channel blocker with efficacy in a rat pain model

Birgit T. Priest; Maria L. Garcia; Richard E. Middleton; Richard M. Brochu; Samantha Clark; Ge Dai; Ivy E. Dick; John P. Felix; Chou J. Liu; Brita S. Reiseter; William A. Schmalhofer; Pengcheng P. Shao; Yui S. Tang; Margaret Z. Chou; Martin G. Kohler; McHardy M. Smith; Vivien A. Warren; Brande S. Williams; Charles J. Cohen; William J. Martin; Peter T. Meinke; William H. Parsons; Keith A. Wafford; Gregory J. Kaczorowski

doi:10.1021/bi0493259

A disubstituted succinamide is a potent sodium channel blocker with efficacy in a rat pain model

Birgit T. Priest, Maria L. Garcia, Richard E. Middleton, Richard M. Brochu, Samantha Clark, Ge Dai, Ivy E. Dick, John P. Felix, Chou J. Liu, Brita S. Reiseter, William A. Schmalhofer, Pengcheng P. Shao, Yui S. Tang, Margaret Z. Chou, Martin G. Kohler, McHardy M. Smith, Vivien A. Warren, Brande S. Williams, Charles J. Cohen, William J. MartinPeter T. Meinke, William H. Parsons, Keith A. Wafford, Gregory J. Kaczorowski

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Abstract

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_V1.2, Na_V1.5, and Na _V1.7 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_V1.2 was 1.2 and 0.14 μM, respectively. BPBTS blocked Na_V1.7 and Na_V1.2 with similar potency, whereas block of Na_V1.5 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 Na_V1.5 (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.

Original language	English (US)
Pages (from-to)	9866-9876
Number of pages	11
Journal	Biochemistry®
Volume	43
Issue number	30
DOIs	https://doi.org/10.1021/bi0493259
State	Published - Aug 3 2004
Externally published	Yes

ASJC Scopus subject areas

Biochemistry

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Priest, B. T., Garcia, M. L., Middleton, R. E., Brochu, R. M., Clark, S., Dai, G., Dick, I. E., Felix, J. P., Liu, C. J., Reiseter, B. S., Schmalhofer, W. A., Shao, P. P., Tang, Y. S., Chou, M. Z., Kohler, M. G., Smith, M. M., Warren, V. A., Williams, B. S., Cohen, C. J., ... Kaczorowski, G. J. (2004). A disubstituted succinamide is a potent sodium channel blocker with efficacy in a rat pain model. Biochemistry®, 43(30), 9866-9876. https://doi.org/10.1021/bi0493259

Priest, BT, Garcia, ML, Middleton, RE, Brochu, RM, Clark, S, Dai, G, Dick, IE, Felix, JP, Liu, CJ, Reiseter, BS, Schmalhofer, WA, Shao, PP, Tang, YS, Chou, MZ, Kohler, MG, Smith, MM, Warren, VA, Williams, BS, Cohen, CJ, Martin, WJ, Meinke, PT, Parsons, WH, Wafford, KA & Kaczorowski, GJ 2004, 'A disubstituted succinamide is a potent sodium channel blocker with efficacy in a rat pain model', Biochemistry®, vol. 43, no. 30, pp. 9866-9876. https://doi.org/10.1021/bi0493259

@article{c1eb9a96c1ec44638e4f0fca9a66010d,

title = "A disubstituted succinamide is a potent sodium channel blocker with efficacy in a rat pain model",

abstract = "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 Na V1.7 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 (Kd = 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.",

author = "Priest, {Birgit T.} and Garcia, {Maria L.} and Middleton, {Richard E.} and Brochu, {Richard M.} and Samantha Clark and Ge Dai and Dick, {Ivy E.} and Felix, {John P.} and Liu, {Chou J.} and Reiseter, {Brita S.} and Schmalhofer, {William A.} and Shao, {Pengcheng P.} and Tang, {Yui S.} and Chou, {Margaret Z.} and Kohler, {Martin G.} and Smith, {McHardy M.} and Warren, {Vivien A.} and Williams, {Brande S.} and Cohen, {Charles J.} and Martin, {William J.} and Meinke, {Peter T.} and Parsons, {William H.} and Wafford, {Keith A.} and Kaczorowski, {Gregory J.}",

year = "2004",

month = aug,

day = "3",

doi = "10.1021/bi0493259",

language = "English (US)",

volume = "43",

pages = "9866--9876",

journal = "Biochemistry{\textregistered}",

issn = "0006-2960",

publisher = "American Chemical Society",

number = "30",

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TY - JOUR

T1 - A disubstituted succinamide is a potent sodium channel blocker with efficacy in a rat pain model

AU - Priest, Birgit T.

AU - Garcia, Maria L.

AU - Middleton, Richard E.

AU - Brochu, Richard M.

AU - Clark, Samantha

AU - Dai, Ge

AU - Dick, Ivy E.

AU - Felix, John P.

AU - Liu, Chou J.

AU - Reiseter, Brita S.

AU - Schmalhofer, William A.

AU - Shao, Pengcheng P.

AU - Tang, Yui S.

AU - Chou, Margaret Z.

AU - Kohler, Martin G.

AU - Smith, McHardy M.

AU - Warren, Vivien A.

AU - Williams, Brande S.

AU - Cohen, Charles J.

AU - Martin, William J.

AU - Meinke, Peter T.

AU - Parsons, William H.

AU - Wafford, Keith A.

AU - Kaczorowski, Gregory J.

PY - 2004/8/3

Y1 - 2004/8/3

N2 - 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 Na V1.7 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 (Kd = 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.

AB - 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 Na V1.7 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 (Kd = 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.

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JO - Biochemistry®

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ER -

A disubstituted succinamide is a potent sodium channel blocker with efficacy in a rat pain model

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