Inhibition of Nav1.7 channel by a novel blocker QLS-81 for alleviation of neuropathic pain

He-ling Niu1, Ya-ni Liu1, Deng-qi Xue2, Li-ying Dong1, Hui-jie Liu1, Jing Wang1, Yi-lin Zheng2, An-ruo Zou3, Li-ming Shao2, KeWei Wang1,3,4
1 Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao 266073, China
2 School of Pharmacy, Fudan University, Shanghai 201203, China
3 Institute of Innovative Drug, Qingdao University, Qingdao 266021, China
4 Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong-Macao Greater Bay Area, Tamar, Hong Kong, China
Correspondence to: Ya-ni Liu:, Li-ming Shao:, KeWei Wang:,
DOI: 10.1038/s41401-021-00682-9
Received: 28 November 2020
Accepted: 14 April 2021
Advance online: 8 June 2021


Voltage-gated sodium channel Nav1.7 robustly expressed in peripheral nociceptive neurons has been considered as a therapeutic target for chronic pain, but there is no selective Nav1.7 inhibitor available for therapy of chronic pain. Ralfinamide has shown anti- nociceptive activity in animal models of inflammatory and neuropathic pain and is currently under phase III clinical trial for neuropathic pain. Based on ralfinamide, a novel small molecule (S)-2-((3-(4-((2-fluorobenzyl) oxy) phenyl) propyl) amino) propanamide (QLS-81) was synthesized. Here, we report the electrophysiological and pharmacodynamic characterization of QLS-81 as a Nav1.7 channel inhibitor with promising anti-nociceptive activity. In whole-cell recordings of HEK293 cells stably expressing Nav1.7, QLS-81 (IC50 at 3.5 ± 1.5 μM) was ten-fold more potent than its parent compound ralfinamide (37.1 ± 2.9 μM) in inhibiting Nav1.7 current. QLS-81 inhibition on Nav1.7 current was use-dependent. Application of QLS-81 (10 μM) caused a hyperpolarizing shift of the fast and slow inactivation of Nav1.7 channel about 7.9 mV and 26.6 mV, respectively, and also slowed down the channel fast and slow inactivation recovery. In dissociated mouse DRG neurons, QLS-81 (10 μM) inhibited native Nav current and suppressed depolarizing current pulse-elicited neuronal firing. Administration of QLS-81 (2, 5, 10 mg· kg−1· d−1, i.p.) in mice for 10 days dose- dependently alleviated spinal nerve injury-induced neuropathic pain and formalin-induced inflammatory pain. In addition, QLS-81 (10 μM) did not significantly affect ECG in guinea pig heart ex vivo; and administration of QLS-81 (10, 20 mg/kg, i.p.) in mice had no significant effect on spontaneous locomotor activity. Taken together, our results demonstrate that QLS-81, as a novel Nav1.7 inhibitor, is efficacious on chronic pain in mice, and it may hold developmental potential for pain therapy.
Keywords: Nav1.7; ralfinamide; QLS-81; neuropathic pain; inflammatory pain; anti-nociception

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