Biperiden is a drug used in Parkinson disease treatment and it serves also as an antiseizures compound in organophosphates poisoning. It acts as antagonist of muscarinic receptor activated by acetylcholine while the enzyme acetylcholinesterase (AChE) cleaves acetylcholine in synaptic junction into choline and acetic acid. This enzyme is inhibited by various compounds; however there has not been proposed evidence about interaction with biperiden molecule. We investigated this interaction using standard Ellman's assay and experimental findings were critically completed with an in silico prediction by SwissDock docking software. Uncompetitive mechanism of action was revealed from Dixon plot and inhibition constant (Ki ) was calculated to be 1.11 mmol/l. The lowest predicted binding energy was -7.84 kcal/mol corresponding to H-bond between biperiden molecule and Tyr 341 residuum in protein structure of AChE. This interaction seems to be further stabilized by π-π interaction with Tyr 72, Trp 286, and Tyr 341. In conclusion, biperiden appears as a very weak inhibitor but it can serve as a lead structure in a pharmacological research.

Faculty of Chemical Technology University of Pardubice Studentska 95 53210 Pardubice Czech Republic

Faculty of Military Health Sciences University of Defence Trebesska 1575 50001 Hradec Kralove Czech Republic

Zobrazit více v PubMed

Pohanka M. Acetylcholinesterase inhibitors: a patent review (2008 present) Expert Opinion on Therapeutic Patents. 2012;22(8):871–886. doi: 10.1517/13543776.2012.701620. PubMed DOI

Pohanka M. Cholinesterases, a target of pharmacology and toxicology. Biomedical Papers of the Medical Faculty of the University Palacký, Olomouc, Czechoslovakia. 2011;155(3):219–230. doi: 10.5507/bp.2011.036. PubMed DOI

Giacobini E. Cholinesterases: new roles in brain function and in alzheimer's disease. Neurochemical Research. 2003;28(3-4):515–522. doi: 10.1023/a:1022869222652. PubMed DOI

Saxena A., Redman A. M. G., Jiang X., Lockridge O., Doctor B. P. Differences in active site gorge dimensions of cholinesterases revealed by binding of inhibitors to human butyrylcholinesterase. Biochemistry. 1997;36(48):14642–14651. doi: 10.1021/bi971425+. PubMed DOI

Darvesh S., Darvesh K. V., McDonald R. S., et al. Carbamates with differential mechanism of inhibition toward acetylcholinesterase and butyrylcholinesterase. Journal of Medicinal Chemistry. 2008;51(14):4200–4212. doi: 10.1021/jm8002075. PubMed DOI

de Los Ríos C. Cholinesterase inhibitors: a patent review (2007–2011) Expert Opinion on Therapeutic Patents. 2012;22(8):853–869. doi: 10.1517/13543776.2012.701619. PubMed DOI

Arduini F., Ricci F., Bourais I., Amine A., Moscone D., Palleschi G. Extraction and detection of pesticides by cholinesterase inhibition in a two-phase system: a strategy to avoid heavy metal interference. Analytical Letters. 2005;38(11):1703–1719. doi: 10.1080/00032710500206970. DOI

Pohanka M. Alzheimer's disease and related neurodegenerative disorders: Implication and counteracting of melatonin. Journal of Applied Biomedicine. 2011;9(4):185–196. doi: 10.2478/v10136-011-0003-6. DOI

Pohanka M. Alzheimer's disease and oxidative stress: a review. Current Medicinal Chemistry. 2014;21(3):356–364. doi: 10.2174/09298673113206660258. PubMed DOI

Pohanka M. Butyrylcholinesterase as a biochemical marker. Bratislava Medical Journal. 2013;114(12):726–734. doi: 10.4149/BLL_2013_153. PubMed DOI

Beckmann H., Moises H. W. The cholinolytic biperiden in depression - An acute placebo controlled study. Archiv für Psychiatrie und Nervenkrankheiten. 1982;231(3):213–220. doi: 10.1007/BF00343291. PubMed DOI

Wezenberg E., Verkes R. J., Sabbe B. G. C., Ruigt G. S. F., Hulstijn W. Modulation of memory and visuospatial processes by biperiden and rivastigmine in elderly healthy subjects. Psychopharmacology. 2005;181(3):582–594. doi: 10.1007/s00213-005-0083-7. PubMed DOI

Kassa J., Fusek J. The influence of anticholinergic drug selection on the efficacy of antidotal treatment of soman-poisoned rats. Toxicology. 2000;154(1-3):67–73. doi: 10.1016/S0300-483X(00)00322-X. PubMed DOI

Kassa J. Importance of cholinolytic drug selection for the efficacy of HI-6 against soman in rats. Toxicology. 1997;116(1-3):147–152. doi: 10.1016/S0300-483X(96)03537-8. PubMed DOI

Eyer P., Worek F., Kiderlen D., et al. Molar absorption coefficients for the reduced ellman reagent: reassessment. Analytical Biochemistry. 2003;312(2):224–227. doi: 10.1016/S0003-2697(02)00506-7. PubMed DOI

Bourne Y., Grassi J., Bougis P. E., Marchot P. Conformational flexibility of the acetylcholinesterase tetramer suggested by X-ray crystallography. Journal of Biological Chemistry. 1999;274(43):30370–30376. doi: 10.1074/jbc.274.43.30370. PubMed DOI

Grosdidier A., Zoete V., Michielin O. SwissDock, a protein-small molecule docking web service based on EADock DSS. Nucleic Acids Research. 2011;39(2):W270–W277. doi: 10.1093/nar/gkr366. PubMed DOI PMC

Pohanka M. Biosensors containing acetylcholinesterase and butyrylcholinesterase as recognition tools for detection of various compounds. Chemical Papers. 2015;69(1):4–16. doi: 10.2478/s11696-014-0542-x. DOI

Karbassi F., Saboury A. A., Khan M. T. H., Choudhary M. I., Saifi Z. S. Mushroom tyrosinase inhibition by two potent uncompetitive inhibitors. Journal of Enzyme Inhibition and Medicinal Chemistry. 2004;19(4):349–353. doi: 10.1080/14756360409162449. PubMed DOI

Anjana R., Vaishnavi M. K., Sherlin D., et al. Aromatic-aromatic interactions in structures of proteins and protein-DNA complexes: a study based on orientation and distance. Bioinformation. 2012;8(24):1220–1224. doi: 10.6026/97320630081220. PubMed DOI PMC

McGaughey G. B., Gagné M., Rappé A. K. Π-Stacking interactions. Alive and well in proteins. The Journal of Biological Chemistry. 1998;273(25):15458–15463. doi: 10.1074/jbc.273.25.15458. PubMed DOI

Colletier J.-P., Fournier D., Greenblatt H. M., et al. Structural insights into substrate traffic and inhibition in acetylcholinesterase. EMBO Journal. 2006;25(12):2746–2756. doi: 10.1038/sj.emboj.7601175. PubMed DOI PMC

Zhao Q., Tang X. C. Effects of huperzine A on acetylcholinesterase isoforms in vitro: Comparison with tacrine, donepezil, rivastigmine and physostigmine. European Journal of Pharmacology. 2002;455(2-3):101–107. doi: 10.1016/S0014-2999(02)02589-X. PubMed DOI

Hollmann M., Brode E., Greger G., Müller-Peltzer H., Wetzelsberger N. Biperiden effects and plasma levels in volunteers. European Journal of Clinical Pharmacology. 1984;27(5):619–621. doi: 10.1007/BF00556903. PubMed DOI

Dieckmann L. H. J., Ramos A. C., Silva E. A., et al. Effects of biperiden on the treatment of cocaine/crack addiction: A randomised, double-blind, placebo-controlled trial. European Neuropsychopharmacology. 2014;24(8):1196–1202. doi: 10.1016/j.euroneuro.2014.06.001. PubMed DOI

Sudo Y., Suhara T., Suzuki K., et al. Muscarinic receptor occupancy by biperiden in living human brain. Life Sciences. 1999;64(8) PubMed

Abalos I. S., Rodríguez Y. I., Lozano V., et al. Transepithelial transport of biperiden hydrochloride in Caco-2 cell monolayers. Environmental Toxicology and Pharmacology. 2012;34(2):223–227. doi: 10.1016/j.etap.2012.04.004. PubMed DOI

Mahar Doan K. M., Humphreys J. E., Webster L. O., et al. Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs. The Journal of Pharmacology and Experimental Therapeutics. 2002;303(3):1029–1037. doi: 10.1124/jpet.102.039255. PubMed DOI

Darreh-Shori T., Meurling L., Pettersson T., et al. Changes in the activity and protein levels of CSF acetylcholinesterases in relation to cognitive function of patients with mild alzheimer's disease following chronic donepezil treatment. Journal of Neural Transmission. 2006;113(11):1791–1801. doi: 10.1007/s00702-006-0526-2. PubMed DOI

Valis M., Masopust J., Vysata O., et al. Concentration of Donepezil in the Cerebrospinal Fluid of AD Patients: Evaluation of Dosage Sufficiency in Standard Treatment Strategy. Neurotoxicity Research. 2017;31(1):162–168. doi: 10.1007/s12640-016-9672-y. PubMed DOI PMC