Discovery of aryl sulfonamide-selective Nav1.7 inhibitors with a highly hydrophobic ethanoanthracene core

Abstract

Nav1.7 channels are mainly distributed in the peripheral nervous system. Blockade of Nav1.7 channels with small-molecule inhibitors in humans might provide pain relief without affecting the central nervous system. Based on the facts that many reported Nav1.7-selective inhibitors contain aryl sulfonamide fragments, as well as a tricyclic antidepressant, maprotiline, has been found to inhibit Nav1.7 channels, we designed and synthesized a series of compounds with ethanoanthracene and aryl sulfonamide moieties. Their inhibitory activity on sodium channels were detected with electrophysiological techniques. We found that compound 10o potently inhibited Nav1.7 channels stably expressed in HEK293 cells (IC 50 = 0.64 ± 0.30 nmol/L) and displayed a high Nav1.7/Nav1.5 selectivity. In mouse small-sized dorsal root ganglion neurons, compound 10o (10, 100 nmol/L) dose-dependently decreased the sodium currents and dramatically suppressed depolarizing current-elicited neuronal discharge. Preliminary in vivo experiments showed that compound 10o possessed good analgesic activity: in a mouse visceral pain model, administration of compound 10o (30−100 mg/kg, i.p.) effectively and dose-dependently suppressed acetic acid-induced writhing.

Prediction and Optimization of NaV1.7 Sodium Channel Inhibitors Based on Machine Learning and Simulated Annealing

“…It selectively inhibits the Na V 1.7 channel but not the Na V 1.4 and 1.5 channel. Many other references reported the selective inhibition of the Na V 1.7 channel. − To achieve that in our optimization process, we can combine classifiers of Na V 1.5 or Na V 1.4 in future work. Another advantage is that building such a simple classifier does not require a lot of data.…”

Mechanisms Underlying Gastrodin Alleviating Vincristine-Induced Peripheral Neuropathic Pain

“…Besides, the effects of GAS on TTX-sensitive sodium current were recorded on DRG neurons. While Na V 1.6 was mainly distributed in medium and large diameter neurons ( Chen et al, 2020 ), the small-diameter neurons that were concerned in this study expressed Na V 1.7 (TTX-sensitive), Na V 1.8 and Na V 1.9 (TTX-resistant) ( Wang et al, 2020 ). In this section, since the current of Na V 1.7 couldn’t be directly observed, the TTX-sensitive sodium current obtained by subtracting the current after TTX processing from the total Na current, indicating the large component of the TTX-sensitive sodium current was Na V 1.7.…”

A Review of Recent Pharmacological Advances in the Management of Diabetes-Associated Peripheral Neuropathy

“…Multiple studies have suggested that a group of molecules called arylsulfonamides could play a significant role in finding a specific inhibitor of the Na V 1.7 isoform [ 63 , 64 ]. Moreover, certain sodium channel blockers such as lidocaine have been shown to enhance the inhibitory effect arylsulfonamides have on Na V 1.7 channels.…”

“…This discovery lead researchers to believe that a selective inhibition of this channel might prove beneficial in pain treatment in various pathological states [61,62]. Multiple studies have suggested that a group of molecules called arylsulfonamides could play a significant role in finding a specific inhibitor of the Na V 1.7 isoform [63,64]. Moreover, certain sodium channel blockers such as lidocaine have been shown to enhance the inhibitory effect arylsulfonamides have on Na V 1.7 channels.…”