Abstract：
OBJECTIVE: The voltage-gated sodium channel isoform NaV1.7 is a high-interest target for the development of non-opioid analgesics due to its preferential expression in pain-sensing neurons. NaV1.7 is also expressed in autonomic neurons, yet its contribution to involuntary visceral reflexes has received limited attention. The small molecule inhibitor ST-2560 was advanced into pain behaviour and cardiovascular models to understand the pharmacodynamic effects of selective inhibition of NaV1.7.
METHODS: Potency of ST-2560 at NaV1.7 and off-target ion channels was evaluated by whole-cell patch-clamp electrophysiology. Effects on nocifensive reflexes were assessed in non-human primate (NHP) behavioural models, employing the chemical capsaicin and mechanical stimuli. Cardiovascular parameters were monitored continuously in freely-moving, telemetered NHPs following administration of vehicle and ST-2560.
RESULTS: ST-2560 is a potent inhibitor (IC50 = 39 nM) of NaV1.7 in primates with ≥1000-fold selectivity over other isoforms of the human NaV1.x family. Following systemic administration, ST-2560 (0.1-0.3 mg·kg-1, s.c.) suppressed noxious mechanical- and chemical-evoked reflexes at free plasma concentrations threefold to fivefold above NaV1.7 IC50. ST-2560 (0.1-1.0 mg·kg-1, s.c.) also produced changes in haemodynamic parameters, most notably a 10- to 20-mmHg reduction in systolic and diastolic arterial blood pressure, at similar exposures.
CONCLUSIONS: Acute pharmacological inhibition of NaV1.7 is antinociceptive, but also has the potential to impact the cardiovascular system. Further work is merited to understand the role of NaV1.7 in autonomic ganglia involved in the control of heart rate and blood pressure, and the effect of selective NaV1.7 inhibition on cardiovascular function.
METHODS: Potency of ST-2560 at NaV1.7 and off-target ion channels was evaluated by whole-cell patch-clamp electrophysiology. Effects on nocifensive reflexes were assessed in non-human primate (NHP) behavioural models, employing the chemical capsaicin and mechanical stimuli. Cardiovascular parameters were monitored continuously in freely-moving, telemetered NHPs following administration of vehicle and ST-2560.
RESULTS: ST-2560 is a potent inhibitor (IC50 = 39 nM) of NaV1.7 in primates with ≥1000-fold selectivity over other isoforms of the human NaV1.x family. Following systemic administration, ST-2560 (0.1-0.3 mg·kg-1, s.c.) suppressed noxious mechanical- and chemical-evoked reflexes at free plasma concentrations threefold to fivefold above NaV1.7 IC50. ST-2560 (0.1-1.0 mg·kg-1, s.c.) also produced changes in haemodynamic parameters, most notably a 10- to 20-mmHg reduction in systolic and diastolic arterial blood pressure, at similar exposures.
CONCLUSIONS: Acute pharmacological inhibition of NaV1.7 is antinociceptive, but also has the potential to impact the cardiovascular system. Further work is merited to understand the role of NaV1.7 in autonomic ganglia involved in the control of heart rate and blood pressure, and the effect of selective NaV1.7 inhibition on cardiovascular function.
摘要：
目的：电压门控钠通道同工型NaV1.7是开发非阿片类镇痛药的高兴趣靶标，因为它在痛觉神经元中优先表达。NaV1.7也在自主神经中表达，然而，它对非自愿性内脏反射的贡献受到了有限的关注。小分子抑制剂ST-2560被推进到疼痛行为和心血管模型中，以了解选择性抑制NaV1.7的药效学作用。
方法：通过全细胞膜片钳电生理学评估了ST-2560在NaV1.7和脱靶离子通道的效力。在非人灵长类动物（NHP）行为模型中评估了对不良反射的影响，使用化学辣椒素和机械刺激。在自由移动的情况下连续监测心血管参数，在施用车辆和ST-2560后遥测NHP。
结果：ST-2560是灵长类动物中NaV1.7的有效抑制剂（IC50=39nM），其选择性比人类NaV1的其他同工型多1000倍。x家族。全身给药后，ST-2560（0.1-0.3mg·kg-1，s.c.）在游离血浆浓度下抑制有害的机械和化学诱发反射，比NaV1.7IC50高出三倍至五倍。ST-2560（0.1-1.0mg·kg-1，s.c.）也产生了血液动力学参数的变化，最值得注意的是收缩压和舒张压降低10到20mmHg，在类似的暴露。
结论：NaV1.7的急性药理抑制作用具有镇痛作用，但也有可能影响心血管系统。需要进一步的工作来了解NaV1.7在控制心率和血压的自主神经节中的作用，以及选择性抑制NaV1.7对心血管功能的影响。
方法：通过全细胞膜片钳电生理学评估了ST-2560在NaV1.7和脱靶离子通道的效力。在非人灵长类动物（NHP）行为模型中评估了对不良反射的影响，使用化学辣椒素和机械刺激。在自由移动的情况下连续监测心血管参数，在施用车辆和ST-2560后遥测NHP。
结果：ST-2560是灵长类动物中NaV1.7的有效抑制剂（IC50=39nM），其选择性比人类NaV1的其他同工型多1000倍。x家族。全身给药后，ST-2560（0.1-0.3mg·kg-1，s.c.）在游离血浆浓度下抑制有害的机械和化学诱发反射，比NaV1.7IC50高出三倍至五倍。ST-2560（0.1-1.0mg·kg-1，s.c.）也产生了血液动力学参数的变化，最值得注意的是收缩压和舒张压降低10到20mmHg，在类似的暴露。
结论：NaV1.7的急性药理抑制作用具有镇痛作用，但也有可能影响心血管系统。需要进一步的工作来了解NaV1.7在控制心率和血压的自主神经节中的作用，以及选择性抑制NaV1.7对心血管功能的影响。
