ReviewDesign and screening of ASIC inhibitors based on aromatic diamidines for combating neurological disorders
Section snippets
ASIC background
ASICs form a branch of the degenerin/epithelial sodium channels (DEG/ENaC) gene family in mammals. ASICs are activated by extracellular low pH. So far ASICs have been identified exclusively in chordates (Grunder and Chen, 2010) and 6 ASIC subunits (ASIC1a, -1b, -2a, -2b, -3 and -4) have been cloned in mammals (Krishtal, 2003, Waldmann et al., 1997). ASICs have widespread distribution to many regions in the nervous system including dorsal root ganglia, cortex, hippocampus, basal ganglia,
ASIC pharmacology
Amiloride, PcTx1, ApeTx2, A-317567 and nafamostat are known ASIC inhibitors. The diuretic amiloride is the prototype blocker of ASICs channels (Grunder and Chen, 2010). Amiloride is not selective for ASICs and it inhibits ENaC, T-type calcium channels and a few others (Xiong et al., 2008). A-317567 was identified by Abbott laboratories (Dube et al., 2005). Nafamostat is a potent protease inhibitor (Fujii & Hitomi, 1981, Ugawa et al., 2007). PcTx1 and ApeTx2 are large-molecule peptide toxins
Aromatic diamidines
Aromatic diamidines are synthetic DNA minor groove binders (Neidle, 2001) (Fig. 2, Fig. 3). This class of agents share common structural features: they are semi-symmetrical, they largely have a crescent shape or the ability to adopt such a shape that complements the minor groove of DNA; they have terminal amidines mounted onto benzene rings that confer positive charges; they have two aromatic diamidines on each side connected by molecular bridges of varying length and composition (Briggaman,
Aromatic diamidines block ASICs potently
The application of aromatic diamidines is not limited to anti-parasitics. Recently, we found that aromatic diamidines such as pentamidine, hydroxystilbamidine, and diminazene potently block ASICs (Chen et al., 2010). Aromatic diamidines comprise a chemical library that contains numerous molecules for identifying selective and potent ASIC inhibitors (Fig. 2, Fig. 4). We found that dicationic agents with variable structures inhibit ASIC activities with different potency (Chen et al., 2010). We
Newly synthesized aromatic diamidines and their (pre-) clinical studies
Given the broad applications of aromatic diamidines, it is conceivable that many efforts have been put to optimize the therapeutic application of aromatic diamidines. This would provide a shortcut for screening selective ASIC inhibitors pharmacological tools or for therapeutic purposes. The management of parasite-infected patients such as HAT using current anti-protozoan drugs including aromatic diamidines is cumbersome and risky, requiring well-trained staff (Simarro et al., 2008). For
Nafamostat, a protease inhibitor, blocks ASICs
Intriguingly a protease inhibitor, nafamostat was recently found to inhibits ASIC activities (Ugawa et al., 2007). Nafamostat (also named Futhan, or FUT-175) is a synthetic, competitive, reversible serine protease inhibitor (Fujii & Hitomi, 1981, Iwama et al., 1998, Mori et al., 2003) (Fig. 4B). It has potent inhibitory effect on a number of proteases, which are part of the coagulation-fibrinolysis system, the kallikrein-kinin system and the complement system. Therefore, nafamostat functions as
Comparison of nafamostat with aromatic diamidines
Both as ASIC inhibitors, nafamostat and aromatic diamidines share many similarities but also have many distinctions. Firstly, Nafamostat, as a potent protease inhibitor, is clinically used in the treatment of acute pancreatitis, as well as other diseases. For treating this disease, a category of anti-protease agents includes nafamostat, aprotinin, gabexate, and ulinastatin (Chen et al., 2007a), among which nafamostat is the only dicationic chemical. Other protease inhibitors such as gabexate do
Identification of binding site(s) of aromatic diamidines on ASICs
As mentioned above, a truncated non-functional mutant of chicken ASIC1 has been crystallized and resolved at a high resolution (1.9 Å) (Jasti et al., 2007). Later a crystal of functional cASIC1 channel was reported by the same group; albeit at a lower 3 Å resolutions (Gonzales et al., 2009). The work of crystallization set a landmark and greatly facilitates the functional and pharmacological study of ASICs (Canessa, 2007, Li et al., 2009, Yang et al., 2009a, Yang et al., 2009b). The ASIC
Conclusions
There is a large number of aromatic diamidines whose effects have not been tested on ASICs. Aromatic diamidines thereby point an ideal direction for screening more potent or selective ASIC inhibitors with therapeutic potentials. A great advancement is that DB829 is able to cross the BBB to enter the central nervous system, setting a template for drug design to combat parasites or to target ASICs in the brain. Thus it is hoped that from a library of aromatic diamidines (analogs as well), an
Acknowledgments
We appreciate Drs. Stefan Gründer, Harold Atwood, Martin Paukert for invaluable critiques and helpful comments. Part of concepts were developed when X.C. was working with Dr. S. Gründer. This work was supported by grants from the Canadian Institutes of Health Research and the Canadian Stroke Network (to J.F.M.), and by a postdoctoral research fellowship from the Heart and Stroke Foundation of Canada and the Canadian Stroke Network (to X.C.).
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2023, European Journal of PharmacologyCitation Excerpt :The main chemical difference between active compounds (nafamostat and sepimostat) and inactive compounds (gabexate and camostat) lies in the absence of the second charged group in the structure of latter compounds (Fig. 1). The necessity of the second charged group for activity against ASIC channels has been already proposed for amidine compounds (Chen et al., 2010a), and our experimental and modeling results further support it. In addition, we described for the first time the molecular mechanisms of action of nafamostat and sepimostat on ASIC channels, and compared them to those of well-known small molecule ASIC channel antagonist diminazene.
Modulators of ASIC1a and its potential as a therapeutic target for age-related diseases
2023, Ageing Research ReviewsCitation Excerpt :They also showed that the sites of action for diminazene and amiloride overlap, with a higher affinity for amiloride. This unusual activities of amiloride and diminazene have increased interest in other analogues containing guanidine groups (Chen et al., 2010a), with 2-guani-dine-4-methylquinazoline (GMQ) an important one. GMQ interacts with ASIC1a, resulting in a pH-dependent acidic shift of activation and steady-state desensitization by approximately 0.2 units (Alijevic and Kellenberger, 2012).
Membrane potential changes occurring upon acidification influence the binding of small-molecule inhibitors to ASIC1a
2019, NeuropharmacologyCitation Excerpt :The best characterized small molecules, such as amiloride and DA, have been reported to inhibit ASIC1a with affinities in the low micromolar to high nanomolar range, respectively (Lingueglia and Lazdunski, 2013). However, they show a poor target and isoform specificity and therefore have a limited use as therapeutic ASIC1a modulators for both central (CNS) and peripheral (PNS) nervous systems pathologies (Chen et al., 2010a). As a result, it is not surprising that there are several drug screening campaigns based on the rational design of these molecules with the final goal to ameliorate their properties (Santos et al., 2015).
New quinoline-arylamidine hybrids: Synthesis, DNA/RNA binding and antitumor activity
2017, European Journal of Medicinal ChemistryCitation Excerpt :It was been concluded that the ability to form a H-bond between the N-diethylamino lateral side chain of CQ and a DNA base may contribute to the DNA intercalative activity of the quinoline nucleus [15,16]. On the other hand, aromatic amidines, DNA-affinic and highly water soluble moieties, have exhibited a wide range of outstanding therapeutic applications, for instance as ACIS inhibitors [17], botulinum neurotoxin A inhibitors [18], and anticancer [19], antiparasitic [20], and antibacterial [21,22] agents. These compounds bind to the DNA minor groove by a combination of ionic, hydrophobic and hydrogen bonding interactions [23].
Some non-conventional biomolecular targets for diamidines. A short survey
2014, Bioorganic and Medicinal ChemistryCitation Excerpt :The structure of those inhibitors is represented in Figure 3. Because it has been hypothesized14 that the highly basic amidine function could play a crucial role in the inhibition of ASICs, novel leads have been identified14–18 namely, 4′,6-diamidino-2-phenylindole14 (14, DAPI, a fluorescent dye that binds to DNA), diminazene19,20 1, pentamidine 4, and hydroxystilbamidine 5. Electrophysiological recordings showed that those derivatives inhibited ASIC current in cultured hippocampal neurons with IC50 values of 2.8; 0.3; 38; and 1.5 μM respectively.16
Research Progress on the Synthesis of Nitrogen-Containing Compounds with Cyanamide as a Building Block
2023, Chinese Journal of Organic Chemistry