A new tacrine based cholinesterase inhibitor, N-(bromobut-3-en-2-yl)-7-methoxy-1,2,3,4-tetrahydroacridin-9-amine (1), was designed and synthesized to interact with specific regions of human acetylcholinesterase and human butyrylcholinesterase. Its inhibitory ability towards cholinesterases was determined and compared to tacrine (THA) and 9-amino-7-methoxy-1,2,3,4-tetrahydroacridine (7-MEOTA). The assessment of IC50 values revealed 1 as a weak inhibitor of both tested enzymes.

Department of Pharmaceutical Chemistry and Drug Control Faculty of Pharmacy in Hradec Kralove Charles University Prague Heyrovskeho 1203 500 05 Hradec Kralove Czech Republic

Zobrazit více v PubMed

Selkoe D.J. Alzheimer's disease: Genes, proteins, and therapy. Physiol. Rev. 2001;81:741–766. doi: 10.1152/physrev.2001.81.2.741. PubMed DOI

Walsh D.M., Selkoe D.J. Deciphering the molecular basis of memory failure in Alzheimer's disease. Neuron. 2004;44:181–193. doi: 10.1016/j.neuron.2004.09.010. PubMed DOI

Davies P., Maloney A.J.F. Selective loss of central cholinergic neurons in Alzheimer's disease. Lancet. 1976;2:1403. doi: 10.1016/S0140-6736(76)91936-X. PubMed DOI

Perry E.K., Perry R.H., Blessed G., Tomlinson B.E. Necropsy evidence of central cholinergic deficits in senile dementia. Lancet. 1997;1:189. doi: 10.1016/S0140-6736(77)91780-9. PubMed DOI

Summers W.K., Majowski L.V., Marsh G.M., Tachiki K., Kling A. Oral tetrahydroacridineamine in long term treatment of senile dementia, Alzheimer type. N. Engl. J. Med. 1986;315:1241–1245. doi: 10.1056/NEJM198611133152001. PubMed DOI

Watkins P.B., Zimmerman H.J., Knapp M.J., Gracon S.I., Lewis K.W. Hepatotoxic effects of tacrine administration in patients with Alzheimer-disease. Jama-J. Am. Med. Assoc. 1994;271:992–998. doi: 10.1001/jama.1994.03510370044030. PubMed DOI

Marx J.L. Alzheimer's drug trial put on hold. Science. 1987;238:1041–1042. doi: 10.1126/science.3317822. PubMed DOI

Ames D.J., Bhathal P.S., Davies B.M., Fraser J.R.E. Hepatotoxicity of tetrahydroacridine. Lancet. 1988;1:887. doi: 10.1016/S0140-6736(88)91636-4. PubMed DOI

Patocka J., Jun D., Kuca K. Possible role of hydroxylated metabolites of tacrine in drug toxicity and therapy of Alzheimer's disease. Curr. Drug Met. 2008;9:332–335. doi: 10.2174/138920008784220619. PubMed DOI

Filip V., Vachek J., Albrecht V., Dvorak I., Dvorakova J., Fusek J., Havluj J. Pharmacokinetics and tolerance of 7-methoxytacrine following the single dose administration in healthy-volunteers. Int. J. Clin. Pharm. Ther. Toxicol. 1991;29:431–436. PubMed

Korabecny J., Holas O., Musilek K., Pohanka M., Opletalova V., Dohnal V., Kuca K. Synthesis and In Vitro Evaluation of New Tacrine Derivates-Bis-Alkylene Linked 7-MEOTA. Lett. Org. Chem. 2010;7:327–331. doi: 10.2174/157017810791130540. DOI

Korabecny J., Musilek K., Holas O., Binder J., Zemek F., Marek J., Pohanka M., Opletalova V., Dohnal V., Kuca K. Synthesis and in vitro evaluation of N-alkyl-7-methoxytacrine hydrochlorides as potential cholinesterase inhibitors in Alzheimer disease. Bioorg. Med. Chem. Lett. 2010;20:6093–6095. doi: 10.1016/j.bmcl.2010.08.044. PubMed DOI

McLennan D.J. A revised transition state spectrum for concerted bimolecular β-eliminations. Tetrahedron. 1975;31:2999. doi: 10.1016/0040-4020(75)80137-2. DOI

Harel M., Schalk I., Ehret-Sabatier L., Bouet F., Goeldner M., Hirth C., Axelsen P.H., Silman I., Sussman J.L. Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase. Proc. Natl. Acad. Sci. USA. 1993;90:9031–9035. doi: 10.1073/pnas.90.19.9031. PubMed DOI PMC

Patocka J. Anticholinesterase activity of 9-amino-7-methoxy-1,2,3,4-tetrahydroacridine and some derivatives and analogues. Sbornik Ved. Prac. VLVDU Hradec Kralove. 1986;102:123–140.

Pohanka M., Jun D., Kuca K. Improvement of acetylcholinesterase-based assay for organophosphates in way of identification by reactivators. Talanta. 2008;77:451–454. doi: 10.1016/j.talanta.2008.06.007. PubMed DOI

Pang Y.-P., Hong F., Quiram P., Jelacic T., Brimijon S. Synthesis of alkylene linked bis-THA and alkylene linked benzyl- THA as highly potent and selective inhibitors and molecular probes of acetylcholinesterase. J. Chem. Soc., Perkin Trans. 1. 1997:171–176. doi: 10.1039/a601642a. DOI

Trott O., Olson A.J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J. Comput. Chem. 2010;31:455–461. doi: 10.1002/jcc.21334. PubMed DOI PMC

[Accessed on 1st October 2010]; Potein crystal structures are available online: http://www.pdb.org.

Morris G.M., Goodsell D.S., Halliday R.S., Huey R., Hart W.E., Belew R.K., Olson A.J. Automated docking using a lamarckian genetic algorithm and and empirical binding free energy function. J. Comput. Chem. 1998;19:1639–1662. doi: 10.1002/(SICI)1096-987X(19981115)19:14<1639::AID-JCC10>3.0.CO;2-B. DOI

Pettersen E.F., Goddard T.D., Huang C.C., Couch G.S., Greenblatt D.M., Meng E.C., Ferrin T.E. UCSF Chimera – A visualization system for exploratory research and analysis. J. Comput. Chem. 2004;25:1605–1612. doi: 10.1002/jcc.20084. PubMed DOI

DeLano W.L. The PyMOL Molecular Graphics System (2002) [Accessed on 1 October 2010]; Available online: http://www.pymol.org/

In Vitro Effects of Cognitives and Nootropics on Mitochondrial Respiration and Monoamine Oxidase Activity

Development of 2-Methoxyhuprine as Novel Lead for Alzheimer's Disease Therapy

Novel Tacrine-Scutellarin Hybrids as Multipotent Anti-Alzheimer's Agents: Design, Synthesis and Biological Evaluation

7-Methoxytacrine-p-Anisidine Hybrids as Novel Dual Binding Site Acetylcholinesterase Inhibitors for Alzheimer's Disease Treatment

7-Methoxytacrine-adamantylamine heterodimers as cholinesterase inhibitors in Alzheimer's disease treatment--synthesis, biological evaluation and molecular modeling studies