Identification of novel NaV1.7 antagonists using high throughput screening platforms

Area of Science:

• Pharmacology and Neuroscience
• Ion Channel Research
• Drug Discovery

Background:

• Congenital Insensitivity to Pain (CIP) involves NaV1.7 channel dysfunction, making it a key target for pain management.
• NaV-channel family's structural similarity complicates the development of selective analgesics, risking cardiotoxicity and seizures.
• Use- or state-dependent drug profiles offer an alternative to structural selectivity by targeting channel gating.

Purpose of the Study:

• To develop a unified screening protocol for NaV1.7 channel antagonists.
• To increase screening efficacy while preserving state- and use-dependent pharmacology.
• To improve the prediction of analgesic compound efficacy and safety.

Main Methods:

• Designed a novel screening protocol combining two stimulation pulses and a slow voltage ramp.
• Simultaneously assessed resting and state-dependent block of NaV1.7 channels.
• Compared the new protocol against existing methods for identifying use- and state-dependent blockers.

Main Results:

• The new protocol effectively filters compounds for state-dependence.
• It enhances the prediction power for identifying use-dependent NaV1.7 channel blockers.
• Demonstrated the protocol's ability to retain relevant state- and use-dependent pharmacology.

Conclusions:

• The merged protocol offers increased screening efficacy for NaV1.7 channel antagonists.
• This approach aids in the development of safer and more effective analgesics.
• Highlights the importance of state- and use-dependent pharmacology in drug design for pain conditions.