Amiloride Analogs as ASIC1a Inhibitors

Area of Science:

• Neuroscience
• Pharmacology
• Biochemistry

Background:

• Acid-sensing ion channels (ASICs), particularly ASIC1a, are implicated in neurological conditions such as stroke, spinal cord injury, and ALS.
• Developing potent ASIC1a inhibitors is crucial for therapeutic intervention in ASIC1a-related diseases.

Purpose of the Study:

• To investigate the inhibitory effects of amiloride analogs on ASIC1a.
• To elucidate structure-activity relationships among amiloride analogs for ASIC1a inhibition.
• To identify potent ASIC1a inhibitors for potential stroke intervention.

Main Methods:

• Whole-cell patch-clamp electrophysiology was employed to measure ASIC1a currents.
• A mouse model of middle cerebral artery occlusion (MCAO)-induced focal ischemia was utilized.
• Surflex-Dock was used for molecular docking of amiloride analogs.

Main Results:

• Amiloride analogs inhibited ASIC1a currents with the potency order: benzamil > phenamil > DMA > amiloride > HMA ≥ MIA > EIPA.
• This potency order was consistent in both expressed ASIC1a and native ASIC currents in cortical neurons.
• Benzamil and EIPA reduced MCAO-induced infarct volume in mice, with benzamil demonstrating higher potency.

Conclusions:

• A benzyl group addition to the terminal guanidinyl group enhanced ASIC1a inhibitory activity.
• Bulky substitutions at the 5-amino position slightly reduced inhibitory activity.
• Benzamil emerged as the most potent ASIC1a inhibitor among the tested amiloride analogs.