Design and screening of ASIC inhibitors based on aromatic diamidines for combating neurological disorders.
Acid sensing ion channels (ASICs) are implicated in various brain functions including learning and memory and are involved in a number of neurological disorders such as pain, ischemic stroke, depression, and multiple sclerosis. We have recently defined ASICs as one of receptor targets of aromatic diamidines in neurons. Aromatic diamidines are DNA-binding agents and have long been used in the treatment of leishmaniasis, trypanosomiasis, pneumocystis pneumonia and babesiosis. Moreover, some aromatic diamidines are used as skin-care and baby products and others have potential to suppress tumor growth or to combat malaria. A large number of aromatic diamidines or analogs have been synthesized. Many efforts are being made to optimize the therapeutic spectrum of aromatic diamidines, i.e. to reduce toxicity, increase oral bioavailability and enhance their penetration of the blood-brain barrier. Aromatic diamidines therefore provide a shortcut of screening for selective ASIC inhibitors with therapeutic potential. Intriguingly nafamostat, a protease inhibitor for treating acute pancreatitis, also inhibits ASIC activities. Aromatic diamidines and nafamostat have many similarities although they belong to distinct classes of medicinal agents for curing different diseases. Here we delineate background, clinical application and drug development of aromatic diamidines that could facilitate the screening for selective ASIC inhibitors for research purposes. Further studies may lead to a drug with therapeutic value and extend the therapeutic scope of aromatic diamidines to combat neurological diseases.
Chen
Xuanmao
X
Department of Physiology, University of Toronto, Canada. xuanmao.chen@utoronto.ca
Orser
Beverley A
BA
MacDonald
John F
JF
D062565:Acid Sensing Ion Channels; D000578:Amidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D000595:Amino Acid Sequence; D000818:Animals; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D009422:Nervous System Diseases / Q000188:drug therapy* / Q000378:metabolism; D015222:Sodium Channels / Q000737:chemistry / Q000378:metabolism
D062565:Acid Sensing Ion Channels; D000578:Amidines; D009419:Nerve Tissue Proteins; D015222:Sodium Channels