Table 3. hNav1.8 Potency (IC50), Selectivity (IC50), and Antiallodynic Effects in Rodent Models of Neuropathic Pain for 3, 13, and 18a.
| hNav1.8 | hNav subtype selectivity | TTX-r Rat DRG | TTX-R human DRG | hERG | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Cmpd | IC50 (μM) | n | IC50 (μM) | n | IC50 (μM) | n | IC50 (μM) | n | IC50 (μM) | Model | Effect significance | Unbound exposure (μM) |
| 3 | 0.19 | 5 | Nav1.1 = 13 | 5 | 0.44 | 4 | 0.31 | 4 | 30 | SNL hypersensitivity | P < 0.05 (equal to 100 mg/kg gabapentin) | 0.25 |
| Nav1.2 = 12.8 | 5 | |||||||||||
| Nav1.5 = 9.0 | 5 | |||||||||||
| Nav1.7 = 19 | 5 | |||||||||||
| 13 | 0.19 | 2 | Nav1.1 = 37 | 2 | 0.54 | 4 | 0.20 | 3 | >30 | TNT mechanical allodynia | SP < 0.05 (comparable to 10 mg/kg pregabalin) | 0.20 |
| Nav1.5 = 37 | 2 | |||||||||||
| Nav1.7 = 36 | 2 | |||||||||||
| 18 | 0.26 | 4 | SHSY5Yb = 10 Nav1.5 = 12 |
5 | 0.33 | 6 | ND | >30 | TNT mechanical allodynia | P < 0.05 (comparable to 10 mg/kg pregabalin) | 0.19 | |
| 4 |
a
IC50 values for 3, 13, and 18 at recombinantly expressed hNav1.8/β1 (Merck Millipore) and at TTX-R in rat and human DRG were determined using manual patch clamp electrophysiology. hNav subtype selectivity for 3 was also measured using manual patch clamp electrophysiology. IC50 values determined using manual patch clamp electrophysiology were determined at the respective V0.5 of inactivation for TTX-R and each channel isoform. For 13 and 18, human sodium channel subtype selectivity was measured using IonWorks Quattro and FRET, respectively.
b
SHSY5Y cells expressing hNav1.2, 1.3, and 1.7 were also used. The voltage protocol for the IonWorks Quattro and assay methodology for the FRET assay is detailed in the Supporting Information.