Amidine derived inhibitors of acid-sensing ion channel-3 (ASIC3)

Abstract

A series of indole amidines modified at the 2-position of the indole ring were evaluated as inhibitors of Acid-Sensing Ion Channel-3 (ASIC3), a novel target for the treatment of chronic pain.

International Union of Basic and Clinical Pharmacology. XCI. Structure, Function, and Pharmacology of Acid-Sensing Ion Channels and the Epithelial Na+Channel

“…In animal pain models, A-317567 was more potent than amiloride. Subsequently, a series of indol amidines was tested for inhibition of ASIC3, identifying compounds inhibiting ASIC3 with an IC 50 ,1 mM that partially reversed mechanical hypersensitivity after paw inflammation (Kuduk et al, 2009a). Different anti-protozoal diarylamidines inhibited ASICs with IC 50 of 0.3-38 mM .…”

Novel Insights into Acid-Sensing Ion Channels: Implications for Degenerative Diseases

“…ASIC1b is almost exclusively expressed in sensory neurons. In contrast, ASIC3 is predominantly expressed in dorsal root ganglia neurons, especially nociceptive sensory neurons [28]. ASIC4, a new member of this ion channel group, exists within inner ear neurons, adenohypophysis, and intervertebral disc [29,30].…”

Discovery and molecular interaction studies of a highly stable, tarantula peptide modulator of acid-sensing ion channel 1

“…10 resulted in more potent molecules against ASICs, however, all had significant off-target effects resulting in substantial sedation in animal studies (Kuduk et al, 2009a;Kuduk et al, 2010;Kuduk et al, 2009b). Based on the discovery of PcTx1 in a spider venom (Escoubas et al, 2000) as well as preliminary screening data from past studies (Escoubas, unpublished) we hypothesized that spider venoms, and especially tarantula venoms, should be a valuable source of additional novel ASIC modulators.…”