Amiloride Analogs as ASIC1a Inhibitors.

Abstract

BACKGROUND:

ASIC1a, the predominant acid-sensing ion channels (ASICs), is implicated in neurological disorders including stroke, traumatic spinal cord injury, and ALS. Potent ASIC1a inhibitors should have promising therapeutic potential for ASIC1a-related diseases.

AIMS:

We examined the inhibitory effects of a number of amiloride analogs on ASIC1a currents, aimed at understanding the structure-activity relationship and identifying potent ASIC1a inhibitors for stroke intervention.

METHODS:

Whole-cell patch-clamp techniques and a mouse model of middle cerebral artery occlusion (MCAO)-induced focal ischemia were used. Surflex-Dock was used to dock the analogs into the pocket with default parameters.

RESULTS:

Amiloride and its analogs inhibit ASIC1a currents expressed in Chinese hamster ovary cells with a potency rank order of benzamil > phenamil > 5-(N,N-dimethyl)amiloride (DMA) > amiloride > 5-(N,N-hexamethylene)amiloride (HMA) ≥ 5-(N-methyl-N-isopropyl)amiloride (MIA) > 5-(N-ethyl-N-isopropyl)amiloride (EIPA). In addition, amiloride and its analogs inhibit ASIC currents in cortical neurons with the same potency rank order. In mice, benzamil and EIPA decreased MCAO-induced infarct volume. Similar to its effect on the ASIC current, benzamil showed a much higher potency than EIPA.

CONCLUSION:

Addition of a benzyl group to the terminal guanidinyl group resulted in enhanced inhibitory activity on ASIC1a. On the other hand, the bulky groups added to the 5-amino residues slightly decreased the activity. Among the tested amiloride analogs, benzamil is the most potent ASIC1a inhibitor.

• Authors: Tian-Dong Leng, Hong-Fang Si, Jun Li, Tao Yang, Mengyuan Zhu, Binghe Wang, Roger P Simon, Zhi-Gang Xiong
• Journal: CNS neuroscience & therapeutics (CNS Neurosci Ther) Vol. 22 Issue 6 Pg. 468-76 (06 2016) ISSN: 1755-5949 [Electronic] England
• PMID: 26890278 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 John Wiley & Sons Ltd.

Chemical References

• Acid Sensing Ion Channels
• Asic1 protein, rat
• Amiloride

Topics

• Acid Sensing Ion Channels (physiology)
• Amiloride (analogs & derivatives, chemistry, pharmacology, therapeutic use)
• Animals
• Biophysics
• CHO Cells
• Cells, Cultured
• Cerebral Cortex (cytology)
• Cricetinae
• Cricetulus
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Electric Stimulation
• Embryo, Mammalian
• Infarction, Middle Cerebral Artery (drug therapy)
• Inhibitory Concentration 50
• Male
• Membrane Potentials (drug effects)
• Mice
• Mice, Inbred C57BL
• Models, Molecular
• Neurons (drug effects)
• Patch-Clamp Techniques
• Transfection