New promising agents against COPD and asthma among the amides of 1-oxo-3-phenyl-isochroman-6-carboxylic acid
Abstract
Background: Bronchodilators, which are compounds that can relax airway smooth muscle, are perhaps the most important component of combination therapy for chronic obstructive pulmonary disease, one of the most common non-communicable diseases in the world, which is the second most lethal disease after cardiovascular disease. Unfortunately, current clinical bronchodilators, whose activity is mediated by their interaction with muscarinic acetylcholine receptors, have side effects (up to myocardial infarction) due to their cross-affinity for different types of these receptors, including those prevalent in the heart muscle.
Objectives: The aim of this work is to search/develop compounds — effective bronchodilators capable of selectively inhibiting type 3 muscarinic acetylcholine receptors (M3 receptors), predominantly present in smooth muscles and not characteristic of cardiomyocytes.
Materials and Methods: High-throughput virtual screening of a collection of 150,000 compounds was conducted on the spatial structure of the M3 receptor, reconstructed in our previous studies. The effect of substances on contractile activity was investigated using tensometry in isometric mode on multicellular tracheal preparations. Antagonistic activity and type of inhibition were determined against the background of acetylcholine application (concentration range 10-10–10-3 M). To establish the affinity value of the compound-antagonist, the Schild regression equation was used.
Results: Based on virtual screening data, a series of compounds — amides of 1-oxo-3-phenyl-iso-chroman-6-carboxylic acid — were selected for biological testing. For two of these compounds (Compounds 1 and 7), the ability to selectively inhibit M3 receptors was demonstrated. Specifically, the affinity value pKB for Compound 1 was 7.28 ± 0.70, with an IC50 of 5.25·10-8 M. A critically important advantage of this compound is its ability, at equal concentrations, to more effectively inhibit signal transmission through M3 receptors compared to ipratropium bromide — a clinical cholinergic receptor inhibitor.
Conclusions: The sufficient effectiveness of inhibition and significantly increased selectivity of the studied compounds specifically towards M3 receptors provide strong grounds to consider these compounds as promising precursors of new generation cholinolytic drugs with targeted action on M3-type cholinergic receptors.
Downloads
References
Cavazos Galván M. Asthma in emergency department. Guidelines, physicians and patients. Rev Alerg Mex. 2006 Jul-Aug;53(4):136–43. Available from: https://pubmed.ncbi.nlm.nih.gov/17137189/
Zeng Z, Mukherjee A, Varghese AP, Yang XL, Chen S, Zhang H. Roles of G protein-coupled receptors in inflammatory bowel disease. World J Gastroenterol. 2020 Mar 28;26(12):1242–61. https://doi.org/10.3748/wjg.v26.i12.1242
Ilyaskina OS, Lemoine H, Bünemann M. Lifetime of muscarinic receptor–G-protein complexes determine coupling efficiency and G-protein subtype selectivity. Proc Natl Acad Sci. 2018 May 8;115(19):5016–21. https://doi.org/10.1073/pnas.1715751115
Saternos HC, Almarghalani DA, Gibson HM, Meqdad MA, Antypas RB, Lingireddy A, et al. Distribution and function of the muscarinic receptor subtypes in the cardiovascular system. Physiol Genomics. 2018 Jan 1;50(1):1–9. https://doi.org/10.1152/physiolgenomics.00062.2017
Ishii M, Kurachi Y. Muscarinic Acetylcholine Receptors. Curr Pharm Des. 2006 Oct 1;12(28):3573–81. https://doi.org/10.2174/138161206778522056
Tobin G, Giglio D, Lundgren O. Muscarinic receptor subtypes in the alimentary tract. J Physiol Pharmacol. 2009 Mar;60(1):3–21. Available from: https://europepmc.org/article/med/19439804
Lee HW, Park J, Jang EJ, Lee CH. Comparisons of exacerbations and mortality among LAMA/LABA combinations in stable chronic obstructive pulmonary disease: systematic review and Bayesian network meta-analysis. Respir Res. 2020 Dec 25;21(1):310. https://doi.org/10.1186/s12931-020-01540-8
Kruse AC, Kobilka BK, Gautam D, Sexton PM, Christopoulos A, Wess J. Muscarinic acetylcholine receptors: novel opportunities for drug development. Nat Rev Drug Discov. 2014 Jul 6;13(7):549–60. https://doi.org/10.1038/nrd4295
Rhee CK, Yoshisue H, Lad R. Fixed-Dose Combinations of Long-Acting Bronchodilators for the Management of COPD: Global and Asian Perspectives. Adv Ther. 2019 Mar 11;36(3):495–519. https://doi.org/10.1007/s12325-019-0893-3
Abrams P, Andersson K, Buccafusco JJ, Chapple C, de Groat WC, Fryer AD, et al. Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder. Br J Pharmacol. 2006 Jul 29;148(5):565–78. https://doi.org/10.1038/sj.bjp.0706780
Eglen RM. Muscarinic Receptor Subtype Pharmacology and Physiology. In: King FD, Lawton G, editors. Progress in Medicinal Chemistry. Vol. 43. Elsevier; 2005. p. 105–36. https://doi.org/10.1016/s0079-6468(05)43004-0
Barnes PJ. Muscarinic receptor subtypes in airways. Life Sci. 1993 Jan;52(5–6):521–7. https://doi.org/10.1016/0024-3205(93)90310-y
Miravitlles M, Anzueto A, Jardim JR. Optimizing bronchodilation in the prevention of COPD exacerbations. Respir Res. 2017 Dec 20;18(1):125. https://doi.org/10.1186/s12931-017-0601-2
Eglen RM. Overview of Muscarinic Receptor Subtypes. In: Muscarinic Receptors. Berlin, Heidelberg: Springer Berlin Heidelberg; 2012. p. 3–28. https://doi.org/10.1007/978-3-642-23274-9_1
Gomes F, Cheng SL. Pathophysiology, Therapeutic Targets, and Future Therapeutic Alternatives in COPD: Focus on the Importance of the Cholinergic System. Biomolecules. 2023 Mar 5;13(3):476. https://doi.org/10.3390/biom13030476
Maqsood MH, Rubab K, Maqsood MA. The Role of Revefenacin in Chronic Obstructive Pulmonary Disease. Cureus. 2019 Apr 10; 11(4):e4428. https://doi.org/10.7759/cureus.4428
Nadler LS, Rosoff ML, Hamilton SE, Kalaydjian AE, McKinnon LA, Nathanson NM. Molecular analysis of the regulation of muscarinic receptor expression and function. Life Sci. 1999 Jan;64(6–7):375–9. https://doi.org/10.1016/s0024-3205(98)00577-3
Zaagsma J, Roffel AF, Meurs H. Muscarinic control of airway function. Life Sci. 1997 Feb;60(13–14):1061–8. https://doi.org/10.1016/s0024-3205(97)00048-9
Nyporko A, Tsymbalyuk O, Voiteshenko I, Starosyla S, Protopopov M, Bdzhola V. Computer‐aided design of muscarinic acetylcholine receptor M3 inhibitors: Promising compounds among trifluoromethyl containing hexahydropyrimidinones/thiones. Mol Inform. 2023 Aug 9;42(8–9). https://doi.org/10.1002/minf.202300006
Abagyan R, Raush E, Totrov M. ICM Manual v.3.9 [Internet]. Molsoft, LLC. [cited 2023 Nov 30]. Available from: https://www.molsoft.com/icm
Protopopov M V., Starosyla SA, Borovykov O V., Sapelkin VN, Bilokin Y V., Bdzhola VG, et al. Hit identification of CK2 inhibitors by virtual screening. Biopolym Cell. 2017 Aug 31;33(4):291–301. https://doi.org/10.7124/bc.00095B
Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem. 2009 Dec 27;30(16):2785–91. https://doi.org/10.1002/jcc.21256
Sheridan RP, Maiorov VN, Holloway MK, Cornell WD, Gao YD. Drug-like Density: A Method of Quantifying the “Bindability” of a Protein Target Based on a Very Large Set of Pockets and Drug-like Ligands from the Protein Data Bank. J Chem Inf Model. 2010 Nov 22;50(11):2029–40. https://doi.org/10.1021/ci100312t
Dassault Systèmes. BIOVIA Discovery Studio Visualizer [Internet]. Dassault Systèmes. 2020 [cited 2023 Nov 30]. Available from: https://discover.3ds.com/discovery-studio-visualizer-download
Tsymbaliuk OV, Naumenko AM, Skoryk MA, Nyporko OYu, Davidovska TL, Skryshevsky VA. Histamine- and nicotine-stimulated modulations of mechanic activity of smooth muscles in gastrointestinal tract at the impact of nanosized TiO2 material. Biopolym Cell. 2016 Apr 30;32(2):140–9. https://doi.org/10.7124/bc.000917
Naumenko AM, Dmytrenko O V., Shapoval LM, Tsymbalyuk O V., Sagach VF, Davydovska TL. Effects of Injections of Nanostructured Titanium Dioxide into the Rat Medullary Nuclei Involved in Cardiovascular Control. Neurophysiology. 2018 Nov 18;50(6):409–14. https://doi.org/10.1007/s11062-019-09772-1
Naumenko AM, Shapoval LM, Nyporko AYu, Voiteshenko MI, Tsymbalyuk A V., Sagach VF, et al. Computer Simulation of Molecular Interaction Between Baclofen and the GABAB Receptor. Neurophysiology. 2017 Feb 1;49(1):2–7. https://doi.org/10.1007/s11062-017-9623-0
Luo L, Zhang G, Mao L, Wang P, Xi C, Shi G, et al. Group II muscarinic acetylcholine receptors attenuate hepatic injury via Nrf2/ARE pathway. Toxicol Appl Pharmacol. 2020 May;395:114978. https://doi.org/10.1016/j.taap.2020.114978
Baroffio M, Crimi E, Brichetto L, Zappi L, Rehder K, Brusasco V. Pre-junctional muscarinic autoreceptors in bovine airways. Respir Physiol Neurobiol. 2012 Jan;180(1):45–51. https://doi.org/10.1016/j.resp.2011.10.007
Naumenko AM, Nyporko AYu, Tsymbalyuk OV, Golius A, Shapoval LM, Davidovska TL. 3D reconstruction of a full-size GABAB receptor. Neurophysiology. 2015;47:364–75. https://doi.org/10.1007/s11062-016-9544-3
Aparici M, Carcasona C, Ramos I, Montero JL, Otal R, Ortiz JL, et al. Pharmacological Profile of AZD8871 (LAS191351), a Novel Inhaled Dual M3 Receptor Antagonist/β2-Adrenoceptor Agonist Molecule with Long-Lasting Effects and Favorable Safety Profile. J Pharmacol Exp Ther. 2019 Jul;370(1):127–36. https://doi.org/10.1124/jpet.118.255620
Authors who publish with this journal agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).
