Objective:

We sought to investigate whether Cilnidipine, a novel  calcium channel blocker (CCB) approved in Asian countries to treat hypertension since 1995, might have activity against  Nav1.7 and compare this with relevant Nav1.7 antagonists used to treat neuropathic pain. 

Background:

Recent investigations demonstrate  N channel antagonists activity at Nav1.7, Nav1.8, TRPV-1 and microglial P2X7, all contributors in neuropathic pain. Cilnidipine is a safe drug long used in hypertension, with an improved safety profile compared with other CCBs. We studied Nav1.7 activity for possible development for neuropathic pain.

Design/Methods:

Voltage gated studies were performed on CHO cells expressing Nav1.7 cells on their surface. Cells were cultured according to the manufacturers SOP and enzymatically lifted into test solutions following an SOP (QPatch II) (Sophion Biosciences).  Baseline measurements were performed to insure cell viability and calibration.   Test agents were measured for activity at a log range of 6 concentrations.   Results were averaged to determine IC50 values.  Testing agents included cilnidipine, amlodipine, gabapentin, nifedipine, bupivicaine, and tetradotoxin. Testing was done over clinically relevant concentrations.   Values were measured in both closed and inactivated states.

Results:

Each microarray test at each of 6 concentrations for each agent was performed (54) times. A total of just over 2,100 voltage gated readings were obtained over the course of the experiment. Cilnidipine was found to more potently inhibit Nav1.7 in the closed state than either gabapentin, amlodipine and bupivicaine. 

Conclusions:

Cilnidipine potently inhibited Nav1.7, with six times the potency at a 20 mg dose than an 1800 mg dose of gabapentin.  Work by Lipscombe suggests that N channel antagonists may have particular utility in peripheral pain conditions and thermal hyperalgesia. Cilnidipine is  being developed to treat Raynaud's symptoms in patients with Systemic Sclerosis, a peripheral pain condition.  This work suggests the drug might have additional development opportunities in other peripheral neuropathic pain treatments.