A-803467

A-803467 is a tetrodotoxin-resistant Na_v1.8 sodium channel blocker which can block human Na_v1.8 with an IC₅₀ of 8nM ^{[1, 2]}. A-803467 can effectively block experimental inflammatory and neuropathic pain caused by the Na_v1.8 channel ^[1].

A-803467 (7.5μM; 2h) enhanced the intracellular [³H]-MX accumulation in ABCG2-transfected HEK293 cells ^[2]; A-803467 (7.5μM; 0, 30, 60, 120min) significantly blocked the intracellular [³H]-MX efflux from ABCG2-transfected cells ^[2]; A-803467 (100nM) caused significant current blocking in HEK-293 cells expressing the human Na_v1.8 sodium channel ^[1]; A-803467 (30nM) shortened action potential in mouse ventricular myocytes at slow frequency (0.1Hz) stimulus current ^[3]; A-803467 (30nM; 15min) reduced frequency of diastolic Ca²⁺ waves in human atrial cardiomyocytes from patients with sinus rhythm ^[4].

A-803467 (10, 30, 100mg/kg; i.p.) potently reduced thermal hyperalgesia in the complete Freund’s adjuvant (CFA) Sprague-Dawley (SD) rat model of inflammatory pain ^[1]; A-803467 (10, 30, 100mg/kg; i.p.) reduced mechanical allodynia in the L5/L6 spinal nerve injury model of SD rats ^[1]; A-803467 (10, 30, 100mg/kg; i.p.) reduced mechanical allodynia in the chronic constriction injury of the sciatic nerve model of SD rats ^[1]; A-803467 (10mg/rat; i.a.) reduced joint pain of male Wistar rats which induced by monoiodoacetate (MIA) ^[5].

References:
[1] Jarvis M F, Honore P, Shieh C C, et al. A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat [J]. Proceedings of the National Academy of Sciences of the United States of America, 2007, 104(20): 8520-8525.
[2] Anreddy N, Patel A, Zhang Y K, et al. A-803467, a tetrodotoxin-resistant sodium channel blocker, modulates ABCG2-mediated MDR in vitro and in vivo [J]. Oncotarget, 2015, 6(36): 39276-39291.
[3] Yang T, Atack T C, Stroud D M, et al. Blocking Scn10a channels in heart reduces late sodium current and is antiarrhythmic [J]. Circulation research, 2012, 111(3): 322-332.
[4] Pabel S, Ahmad S, Tirilomis P, et al. Inhibition of Na_v1.8 prevents atrial arrhythmogenesis in human and mice [J]. Basic research in cardiology, 2020, 115(2): 20.
[5] Schuelert N, McDougall J J. Involvement of Na_v1.8 sodium ion channels in the transduction of mechanical pain in a rodent model of osteoarthritis [J]. Arthritis research & therapy, 2012, 14(1): R5.

A-803467是一种河豚毒素耐受型Na_v1.8钠通道的阻断剂，其阻断人Na_v1.8钠通道的IC₅₀为8nM^{[1, 2]}。A-803467可以有效阻断Na_v1.8 通道导致的实验性炎症和神经性疼痛^[1]。

A-803467（7.5μM；2h）增加了ABCG2转染的HEK293细胞内[³H]-MX的积累^[2]；A-803467（7.5μM；0、30、60、120min）显著阻断ABCG2转染的HEK293细胞内的[³H]-MX外流^[2]；A-803467（100nM）使表达人Na_v1.8钠通道的HEK-293细胞产生了明显的电流阻滞^[1]；A-803467 （30nM）在慢频率（0.1Hz）的刺激电流下可以缩短小鼠心室肌细胞的动作电位^[3]；A-803467 （30nM；15min）降低了窦性心律患者的人心房心肌细胞的舒张压 Ca²⁺波频率^[4]。

A-803467（10、30、100mg/kg；i.p.）可以有效减轻CFA（complete Freund’s adjuvant）诱导的SD大鼠（Sprague-Dawley）炎症性疼痛模型的热痛觉过敏^[1]；A-803467（10、30、100mg/kg；i.p,）可减轻L5/L6脊髓神经损伤SD大鼠模型的触诱发痛^[1]；A-803467（10、30、100mg/kg；i.p,）可减轻坐骨神经慢性收缩损伤SD大鼠模型的触诱发痛^[1]；A-803467（10mg/只；i.a.）可以减轻MIA（monoiodoacetate）诱导的雄性Wistar大鼠的关节疼痛^[5]。