THE SELECTIVE P2X3R ANTAGONIST DT-0111 DOES NOT AFFECT TASTE IN MICE
Main Article Content
Abstract
Adenosine 5’-triphosphate (ATP) is found in every cell of the human body where it plays a critical role in cellular energetics and metabolism. ATP is released from cells under physiological and pathophysiological conditions. Extracellular ATP acts as an autocrine and paracrine molecule, the effects of which are mediated by cell surface purinergic receptors (P2R). The activation of P2X3R and P2X2/3R localized on vagal sensory nerve terminals has been implicated in the sensation of pain as well as multiple pulmonary disorders including chronic obstructive pulmonary disease (COPD), asthma and chronic cough. DT-0111 is a novel water-soluble molecule that is being developed as a drug candidate for cough suppression and bronchodilation. DT-0111 acts as a selective antagonist at P2X3R vs. P2X2/3R. Because the latter participates in taste sensation, its blockade could explain loss of taste sensation by certain drug candidates targeting P2X3R. Thus, we tested the hypothesis that DT-0111 does not affect taste sensation in a mouse model in vivo. Using the mice-gustometer model, we found that at doses up to x15 the targeted clinical dose (0.142 mg/kg), DT-0111 did not affect taste sensation.
Article Details
How to Cite
PELLEG, Amir et al.
THE SELECTIVE P2X3R ANTAGONIST DT-0111 DOES NOT AFFECT TASTE IN MICE.
Medical Research Archives, [S.l.], v. 13, n. 5, may 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6527>. Date accessed: 21 june 2025.
doi: https://doi.org/10.18103/mra.v13i5.6527.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Greiner JV, Glonek T. Intracellular ATP Concentration and Implication for Cellular Evolution. Biology (Basel) 2021;10(11). DOI: 10.3390/biology1 0111166.
2. Taruno A. ATP Release Channels. Int J Mol Sci 2018;19(3). DOI: 10.3390/ijms19030808.
3. Rahman M, Sun R, Mukherjee S, Nilius B, Janssen LJ. TRPV4 Stimulation Releases ATP via Pannexin Channels in Human Pulmonary Fibroblasts. Am J Respir Cell Mol Biol 2018;59(1):87-95. DOI: 10.1165/rcmb.2017-0413OC.
4. Pelleg A, Schulman ES. Adenosine 5'-Triphosphate Axis in Obstructive Airway Diseases. Am J Therap 2002;9(5):454-464. (http://dx.doi.org/10.1097/00045391-200209000-00014).
5. Bodin P, Burnstock G. Purinergic signalling: ATP release. Neurochem Res 2001;26(8-9):959-69. DOI: 10.1023/a:1012388618693.
6. Idzko M, Hammad H, van Nimwegen M, et al. Extracellular ATP triggers and maintains asthmatic airway inflammation by activating dendritic cells. Nature Med 2007;13(8):913-919.
(http://dx.doi.org/10.1038/nm1617).
7. Zimmermann H. Extracellular metabolism of ATP and other nucleotides. Naunyn-Schmiedeberg's Arch Pharmacol 2000;362(4-5):299-309. (http://dx.doi.org/10.1007/s002100000309).
8. Zimmermann H, Zebisch M, Strater N. Cellular function and molecular structure of ecto-nucleotidases. Purinergic Signal 2012;8(3):437-502. DOI: 10.1007/s11302-012-9309-4.
9. Burnstock G. Purine and pyrimidine receptors. Cell Mol Life Sci 2007;64(12):1471-1483.
(http://dx.doi.org/10.1007/s00018-007-6497-0).
10. Kennedy C. The P2Y/P2X divide: How it began. Biochem Pharmacol 2021;187:114408. DOI: 10.1016/j.bcp.2021.114408.
11. von Kugelgen I, Hoffmann K. Pharmacology and structure of P2Y receptors. Neuropharmacology 2016;104:50-61. DOI: 10.1016/j.neuropharm.2015.1 0.030.
12. Jarvis MF, Khakh BS. ATP-gated P2X cation-channels. Neuropharmacology 2009;56(1):208-15. DOI: 10.1016/j.neuropharm.2008.06.067.
13. North RA. P2X receptors. Philos Trans R Soc Lond B Biol Sci 2016;371(1700). DOI: 10.1098/rstb.2 015.0427.
14. Inoue K. The Role of ATP Receptors in Pain Signaling. Neurochem Res 2022;47(9):2454-2468. DOI: 10.1007/s11064-021-03516-6.
15. Pelleg A, Hurt CM. Mechanism of action of ATP on canine pulmonary vagal C fibre nerve terminals. The Journal of physiology 1996;490 ( Pt 1):265-75. (http://www.ncbi.nlm.nih.gov/pubmed/8745294).
16. Pellegrino R, Wilson O, Jenouri G, Rodarte JR. Lung mechanics during induced bronchoconstriction. J Appl Physiol (1985) 1996;81(2):964-75. DOI: 10.11 52/jappl.1996.81.2.964.
17. Katchanov G, Xu J, Schulman ES, Pelleg A. ATP causes neurogenic bronchoconstriction in the dog. Drug Dev Res 1998;45(3-4):342-349.
(http://dx.doi.org/10.1002/(sici)1098-2299(199811/12)45:3/4<342::aid-ddr34>3.0.co;2-p).
18. Pelleg A, Schulman ES, Barnes PJ. Extracellular Adenosine 5'-Triphosphate in Obstructive Airway Diseases. Chest 2016;150(4):908-915. DOI: 10.1016/j.chest.2016.06.045.
19. Kamei J, Takahashi Y, Yoshikawa Y, Saitoh A. Involvement of P2X receptor subtypes in ATP-induced enhancement of the cough reflex sensitivity. Eur J Pharmacol 2005;528(1-3):158-161.
(http://dx.doi.org/10.1016/j.ejphar.2005.10.030).
20. Kamei J, Takahashi Y. Involvement of ionotropic purinergic receptors in the histamine-induced enhancement of the cough reflex sensitivity in guinea pigs. Eur J Pharmacol 2006;547(1-3):160-4. DOI: 10.1016/j.ejphar.2006.07.034.
21. Pelleg A, Xu F, Zhuang J, Undem B, Burnstock G. DT-0111: a novel drug-candidate for the treatment of COPD and chronic cough. Ther Adv Respir Dis 2019;13:1753466619877960. DOI: 10.1177/1753466619877960.
22. Pelleg A U, BJ. A-317491 Inhibits the activation of guinea-pig pulmonary vagal sensory nerve terminals by α,β methylene_ATP. Clin Immunol 2005;115(Suppl 1):S59-60.
23. Kwong K, Kollarik M, Nassenstein C, Ru F, Undem BJ. P2X2 receptors differentiate placodal vs. neural crest C-fiber phenotypes innervating guinea pig lungs and esophagus. AJP: Lung Cell Mol Physiol 2008;295(5):L858-L865.
(http://dx.doi.org/10.1152/ajplung.90360.2008).
24. Irwin R, Madison, JM. Uexplained or refractory chronic cough in adults. N Engl J Med 2025;392:1203-14. (Review). DOI: 10.1056/NEJMr a2309906.
25. Dicpinigaitis PV, McGarvey LP, Canning BJ. P2X3-Receptor Antagonists as Potential Antitussives: Summary of Current Clinical Trials in Chronic Cough. Lung 2020;198(4):609-616. DOI: 10.1007/s 00408-020-00377-8.
26. Smith JA. The Therapeutic Landscape in Chronic Cough. Lung 2024;202(1):5-16. DOI: 10.100 7/s00408-023-00666-y.
27. Flammer LJ, Ellis H, Rivers N, et al. Topical application of a P2X2/P2X3 purine receptor inhibitor suppresses the bitter taste of medicines and other taste qualities. Br J Pharmacol 2024;181(17):3282-3299. DOI: 10.1111/bph.16411.
28. Finger TE, Danilova V, Barrows J, et al. ATP signaling is crucial for communication from taste buds to gustatory nerves. Science 2005;310(5753): 1495-9. DOI: 10.1126/science.1118435.
29. Pelleg A, Barnes PJ, Schulman ES. Targeting the ATP-axis in lungs as a new therapeutic modality for COPD. Med Res Arch 2023;11(10). DOI: 10.18103/m ra.v11i10.4487.
30. Pelleg A, Sirtori E, Rolland JF, Mahadevan A. DT-0111: a novel P2X3 receptor antagonist. Purinergic Signal 2023. DOI: 10.1007/s11302-023-09930-5.
31. Ma Z, Taruno A, Ohmoto M, et al. CALHM3 Is Essential for Rapid Ion Channel-Mediated Purinergic Neurotransmission of GPCR-Mediated Tastes. Neuron 2018;98(3):547-561 e10. DOI: 10.1016/j.neuron.20 18.03.043.
32. Taruno A, Vingtdeux V, Ohmoto M, et al. CALHM1 ion channel mediates purinergic neurotransmission of sweet, bitter and umami tastes. Nature 2013;495(7440):223-6. DOI: 10.1038/natur e11906.
33. Jacobson KA, AP IJ, Muller CE. Medicinal chemistry of P2 and adenosine receptors: Common scaffolds adapted for multiple targets. Biochem Pharmacol 2021;187:114311. DOI: 10.1016/j.bcp.2 020.114311.
34. Kong Q, Quan Y, Tian G, Zhou J, Liu X. Purinergic P2 Receptors: Novel Mediators of Mechanotransduction. Front Pharmacol 2021;12: 671809. DOI: 10.3389/fphar.2021.671809.
35. Vultaggio-Poma V, Falzoni S, Salvi G, Giuliani AL, Di Virgilio F. Signalling by extracellular nucleotides in health and disease. Biochim Biophys Acta Mol Cell Res 2022;1869(5):119237. DOI: 10.101 6/j.bbamcr.2022.119237.
36. Pelleg A. Extracellular adenosine 5'-triphosphate in pulmonary disorders. Biochem Pharmacol 2021;187:114319. DOI: 10.1016/j.bcp.2 020.114319.
37. Huerta MA, Marcos-Frutos D, Nava J, Garcia-Ramos A, Tejada MA, Roza C. P2X3 and P2X2/3 receptors inhibition produces a consistent analgesic efficacy: A systematic review and meta-analysis of preclinical studies. Eur J Pharmacol 2024;984:177052. DOI: 10.1016/j.ejphar.2024.177 052.
38. Ramadan A, El-Samahy M, Elrosasy A, et al. Safety and efficacy of P2X3 receptor antagonist for the treatment of refractory or unexplained chronic cough: A systematic review and meta-analysis of 11 randomized controlled trials. Pulm Pharmacol Ther 2023;83:102252. DOI: 10.1016/j.pupt.2023.102252.
39. High B, Jette ME, Li M, et al. Variability in P2X receptor composition in human taste nerves: implications for treatment of chronic cough. ERJ Open Res 2023;9(2). DOI: 10.1183/23120541.000 07-2023.
40. Garceau D, Chauret N. BLU-5937: A selective P2X3 antagonist with potent anti-tussive effect and no taste alteration. Pulm Pharmacol Ther 2019;56: 56-62. DOI: 10.1016/j.pupt.2019.03.007.
41. Thach T, Dhanabalan K, Nandekar PP, et al. Mechanistic insights into the selective targeting of P2X3 receptor by camlipixant antagonist. The Journal of biological chemistry 2025;301(1):108109. DOI: 10.1016/j.jbc.2024.108109.
2. Taruno A. ATP Release Channels. Int J Mol Sci 2018;19(3). DOI: 10.3390/ijms19030808.
3. Rahman M, Sun R, Mukherjee S, Nilius B, Janssen LJ. TRPV4 Stimulation Releases ATP via Pannexin Channels in Human Pulmonary Fibroblasts. Am J Respir Cell Mol Biol 2018;59(1):87-95. DOI: 10.1165/rcmb.2017-0413OC.
4. Pelleg A, Schulman ES. Adenosine 5'-Triphosphate Axis in Obstructive Airway Diseases. Am J Therap 2002;9(5):454-464. (http://dx.doi.org/10.1097/00045391-200209000-00014).
5. Bodin P, Burnstock G. Purinergic signalling: ATP release. Neurochem Res 2001;26(8-9):959-69. DOI: 10.1023/a:1012388618693.
6. Idzko M, Hammad H, van Nimwegen M, et al. Extracellular ATP triggers and maintains asthmatic airway inflammation by activating dendritic cells. Nature Med 2007;13(8):913-919.
(http://dx.doi.org/10.1038/nm1617).
7. Zimmermann H. Extracellular metabolism of ATP and other nucleotides. Naunyn-Schmiedeberg's Arch Pharmacol 2000;362(4-5):299-309. (http://dx.doi.org/10.1007/s002100000309).
8. Zimmermann H, Zebisch M, Strater N. Cellular function and molecular structure of ecto-nucleotidases. Purinergic Signal 2012;8(3):437-502. DOI: 10.1007/s11302-012-9309-4.
9. Burnstock G. Purine and pyrimidine receptors. Cell Mol Life Sci 2007;64(12):1471-1483.
(http://dx.doi.org/10.1007/s00018-007-6497-0).
10. Kennedy C. The P2Y/P2X divide: How it began. Biochem Pharmacol 2021;187:114408. DOI: 10.1016/j.bcp.2021.114408.
11. von Kugelgen I, Hoffmann K. Pharmacology and structure of P2Y receptors. Neuropharmacology 2016;104:50-61. DOI: 10.1016/j.neuropharm.2015.1 0.030.
12. Jarvis MF, Khakh BS. ATP-gated P2X cation-channels. Neuropharmacology 2009;56(1):208-15. DOI: 10.1016/j.neuropharm.2008.06.067.
13. North RA. P2X receptors. Philos Trans R Soc Lond B Biol Sci 2016;371(1700). DOI: 10.1098/rstb.2 015.0427.
14. Inoue K. The Role of ATP Receptors in Pain Signaling. Neurochem Res 2022;47(9):2454-2468. DOI: 10.1007/s11064-021-03516-6.
15. Pelleg A, Hurt CM. Mechanism of action of ATP on canine pulmonary vagal C fibre nerve terminals. The Journal of physiology 1996;490 ( Pt 1):265-75. (http://www.ncbi.nlm.nih.gov/pubmed/8745294).
16. Pellegrino R, Wilson O, Jenouri G, Rodarte JR. Lung mechanics during induced bronchoconstriction. J Appl Physiol (1985) 1996;81(2):964-75. DOI: 10.11 52/jappl.1996.81.2.964.
17. Katchanov G, Xu J, Schulman ES, Pelleg A. ATP causes neurogenic bronchoconstriction in the dog. Drug Dev Res 1998;45(3-4):342-349.
(http://dx.doi.org/10.1002/(sici)1098-2299(199811/12)45:3/4<342::aid-ddr34>3.0.co;2-p).
18. Pelleg A, Schulman ES, Barnes PJ. Extracellular Adenosine 5'-Triphosphate in Obstructive Airway Diseases. Chest 2016;150(4):908-915. DOI: 10.1016/j.chest.2016.06.045.
19. Kamei J, Takahashi Y, Yoshikawa Y, Saitoh A. Involvement of P2X receptor subtypes in ATP-induced enhancement of the cough reflex sensitivity. Eur J Pharmacol 2005;528(1-3):158-161.
(http://dx.doi.org/10.1016/j.ejphar.2005.10.030).
20. Kamei J, Takahashi Y. Involvement of ionotropic purinergic receptors in the histamine-induced enhancement of the cough reflex sensitivity in guinea pigs. Eur J Pharmacol 2006;547(1-3):160-4. DOI: 10.1016/j.ejphar.2006.07.034.
21. Pelleg A, Xu F, Zhuang J, Undem B, Burnstock G. DT-0111: a novel drug-candidate for the treatment of COPD and chronic cough. Ther Adv Respir Dis 2019;13:1753466619877960. DOI: 10.1177/1753466619877960.
22. Pelleg A U, BJ. A-317491 Inhibits the activation of guinea-pig pulmonary vagal sensory nerve terminals by α,β methylene_ATP. Clin Immunol 2005;115(Suppl 1):S59-60.
23. Kwong K, Kollarik M, Nassenstein C, Ru F, Undem BJ. P2X2 receptors differentiate placodal vs. neural crest C-fiber phenotypes innervating guinea pig lungs and esophagus. AJP: Lung Cell Mol Physiol 2008;295(5):L858-L865.
(http://dx.doi.org/10.1152/ajplung.90360.2008).
24. Irwin R, Madison, JM. Uexplained or refractory chronic cough in adults. N Engl J Med 2025;392:1203-14. (Review). DOI: 10.1056/NEJMr a2309906.
25. Dicpinigaitis PV, McGarvey LP, Canning BJ. P2X3-Receptor Antagonists as Potential Antitussives: Summary of Current Clinical Trials in Chronic Cough. Lung 2020;198(4):609-616. DOI: 10.1007/s 00408-020-00377-8.
26. Smith JA. The Therapeutic Landscape in Chronic Cough. Lung 2024;202(1):5-16. DOI: 10.100 7/s00408-023-00666-y.
27. Flammer LJ, Ellis H, Rivers N, et al. Topical application of a P2X2/P2X3 purine receptor inhibitor suppresses the bitter taste of medicines and other taste qualities. Br J Pharmacol 2024;181(17):3282-3299. DOI: 10.1111/bph.16411.
28. Finger TE, Danilova V, Barrows J, et al. ATP signaling is crucial for communication from taste buds to gustatory nerves. Science 2005;310(5753): 1495-9. DOI: 10.1126/science.1118435.
29. Pelleg A, Barnes PJ, Schulman ES. Targeting the ATP-axis in lungs as a new therapeutic modality for COPD. Med Res Arch 2023;11(10). DOI: 10.18103/m ra.v11i10.4487.
30. Pelleg A, Sirtori E, Rolland JF, Mahadevan A. DT-0111: a novel P2X3 receptor antagonist. Purinergic Signal 2023. DOI: 10.1007/s11302-023-09930-5.
31. Ma Z, Taruno A, Ohmoto M, et al. CALHM3 Is Essential for Rapid Ion Channel-Mediated Purinergic Neurotransmission of GPCR-Mediated Tastes. Neuron 2018;98(3):547-561 e10. DOI: 10.1016/j.neuron.20 18.03.043.
32. Taruno A, Vingtdeux V, Ohmoto M, et al. CALHM1 ion channel mediates purinergic neurotransmission of sweet, bitter and umami tastes. Nature 2013;495(7440):223-6. DOI: 10.1038/natur e11906.
33. Jacobson KA, AP IJ, Muller CE. Medicinal chemistry of P2 and adenosine receptors: Common scaffolds adapted for multiple targets. Biochem Pharmacol 2021;187:114311. DOI: 10.1016/j.bcp.2 020.114311.
34. Kong Q, Quan Y, Tian G, Zhou J, Liu X. Purinergic P2 Receptors: Novel Mediators of Mechanotransduction. Front Pharmacol 2021;12: 671809. DOI: 10.3389/fphar.2021.671809.
35. Vultaggio-Poma V, Falzoni S, Salvi G, Giuliani AL, Di Virgilio F. Signalling by extracellular nucleotides in health and disease. Biochim Biophys Acta Mol Cell Res 2022;1869(5):119237. DOI: 10.101 6/j.bbamcr.2022.119237.
36. Pelleg A. Extracellular adenosine 5'-triphosphate in pulmonary disorders. Biochem Pharmacol 2021;187:114319. DOI: 10.1016/j.bcp.2 020.114319.
37. Huerta MA, Marcos-Frutos D, Nava J, Garcia-Ramos A, Tejada MA, Roza C. P2X3 and P2X2/3 receptors inhibition produces a consistent analgesic efficacy: A systematic review and meta-analysis of preclinical studies. Eur J Pharmacol 2024;984:177052. DOI: 10.1016/j.ejphar.2024.177 052.
38. Ramadan A, El-Samahy M, Elrosasy A, et al. Safety and efficacy of P2X3 receptor antagonist for the treatment of refractory or unexplained chronic cough: A systematic review and meta-analysis of 11 randomized controlled trials. Pulm Pharmacol Ther 2023;83:102252. DOI: 10.1016/j.pupt.2023.102252.
39. High B, Jette ME, Li M, et al. Variability in P2X receptor composition in human taste nerves: implications for treatment of chronic cough. ERJ Open Res 2023;9(2). DOI: 10.1183/23120541.000 07-2023.
40. Garceau D, Chauret N. BLU-5937: A selective P2X3 antagonist with potent anti-tussive effect and no taste alteration. Pulm Pharmacol Ther 2019;56: 56-62. DOI: 10.1016/j.pupt.2019.03.007.
41. Thach T, Dhanabalan K, Nandekar PP, et al. Mechanistic insights into the selective targeting of P2X3 receptor by camlipixant antagonist. The Journal of biological chemistry 2025;301(1):108109. DOI: 10.1016/j.jbc.2024.108109.