ST‐2560, a selective inhibitor of the NaV1.7 sodium channel, affects nocifensive and cardiovascular reflexes in non‐human primates

• Published in: British journal of pharmacology 2024-09, Vol.181 (17), p.3160-3171
• Main Authors: Mulcahy, John V., Beckley, Jacob T., Klas, Sheri D., Odink, Debra A., Delwig, Anton, Pajouhesh, Hassan, Monteleone, Dennis, Zhou, Xiang, Du Bois, Justin, Yeomans, David C., Luu, George, Hunter, John C.
• Format: Article
• Language: English
• Subjects: Analgesics; Animal models; Autonomic ganglia; Autonomic nervous system; behavioural pharmacology; Blood pressure; Capsaicin; Cardiovascular system; drug discovery/target validation; Electrophysiology; Heart rate; Ion channels; Isoforms; Mechanical properties; Mechanical stimuli; Molecular modelling; NaV1.7; Pain; Pain perception; Pharmacodynamics; Reflexes; Sodium channels (voltage-gated)
• ISSN: 0007-1188; 1476-5381; 1476-5381
• DOI: 10.1111/bph.16398

Background and Purpose 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. Experimental Approach 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. Key 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 and Implications 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.