Synthesis, Structure−Activity Relationship, and Pharmacological Profile of Analogs of The ASIC-3 Inhibitor A-317567

Abstract

The synthesis, structure-activity relationship (SAR), and pharmacological evaluation of analogs of the acid-sensing ion channel (ASIC) inhibitor A-317567 are reported. It was found that the compound with an acetylenic linkage was the most potent ASIC-3 channel blocker. This compound reversed mechanical hypersensitivity in the rat iodoacetate model of osteoarthritis pain, although sedation was noted. Sedation was also observed in ASIC-3 knockout mice, questioning whether sedation and antinociception are mediated via a non-ASIC-3 specific mechanism.

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of PcTx1 in a spider venom (Escoubas et al, 2000) as well as preliminary screening data from past studies (Escoubas, unpublished) we hypothesized that spider venoms, and especially tarantula venoms, should be a valuable source of additional novel ASIC modulators.…”

Pharmacology of ASIC channels

“…The amidine A‐317567 (Figure ) has been described as a nonamiloride and more specific inhibitor of ASICs, with IC 50 ranging from 2 to 30 µM on the different native ASIC currents in DRG neurons . An IC 50 of ∼1 µM has been evaluated on HEK293 cells expressing the human ASIC3 channel using an automated patch clamp assay . A close analog of A‐317567 inhibits recombinant human ASIC3 and ASIC1a with a better potency (IC 50 ∼356 and 450 nM, respectively) .…”

“…An IC 50 of ∼1 µM has been evaluated on HEK293 cells expressing the human ASIC3 channel using an automated patch clamp assay . A close analog of A‐317567 inhibits recombinant human ASIC3 and ASIC1a with a better potency (IC 50 ∼356 and 450 nM, respectively) . However, this compound interacts (IC 50 's < 10 µM) with a number of neurotransmitter receptors including muscarinic, adrenergic, dopamine, norepinephrine, and serotonin receptors, suggesting possible off‐target effects when used in vivo .…”

“…A close analog of A‐317567 inhibits recombinant human ASIC3 and ASIC1a with a better potency (IC 50 ∼356 and 450 nM, respectively) . However, this compound interacts (IC 50 's < 10 µM) with a number of neurotransmitter receptors including muscarinic, adrenergic, dopamine, norepinephrine, and serotonin receptors, suggesting possible off‐target effects when used in vivo . The amidine moiety of A‐317567 is critical for the inhibitory effect on ASIC3 current, and an evaluation of a series of indole amidines modified at the two‐position of the indole ring led to the discovery of a more potent ASIC3 blocker (IC 50 ∼133 nM) .…”

Subtype‐selective inhibition of acid‐sensing ion channel 3 by a natural flavonoid

“…It blocks all kinds of ASIC currents with the IC 50 value to be 10‐20 μmol/L. Compound 2 which belongs to arylamidine family is the first nonamiloride inhibitor with relatively high ASIC3 selectivity (IC 50 : 2‐30 μmol/L) . Arylamidine 3 reversibly blocks ASIC1a, ASIC2a, and ASIC3 channels (IC 50 : 2‐70 μmol/L) .…”