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. 2009 Jan;6(1):152–162. doi: 10.1016/j.nurt.2008.10.042

Memoquin: A multi-target-directed ligand as an innovative therapeutic opportunity for Alzheimer’s disease

Maria Laura Bolognesi 1,✉, Andrea Cavalli 1,2,✉, Carlo Melchiorre 1
PMCID: PMC5084263  PMID: 19110206

Summary

Alzheimer’s disease is currently thought to be a complex, multifactorial syndrome, unlikely to arise from a single causal factor; instead, a number of related biological alterations are thought to contribute to its pathogenesis. This may explain why the currently available drugs, developed according to the classic drug discovery paradigm of “one-molecule-one-target,” have turned out to be palliative. In light of this, drug combinations that can act at different levels of the neurotoxic cascade offer new avenues toward curing Alzheimer’s and other neurodegenerative diseases. In parallel, a new strategy is emerging—that of developing a single chemical entity able to modulate multiple targets simultaneously. This has led to a new paradigm in medicinal chemistry, the “multi-target-directed ligand” design strategy, which has already been successfully exploited at both academic and industrial levels. As a case study, we report here on memoquin, a new molecule developed following this strategy. The in vitro and in vivo biological profile of memoquin demonstrates the suitability of the new strategy for obtaining innovative drug candidates for the treatment of neurodegenerative diseases.

Key Words: Multifunctional compounds, AD11 mice, acetylcholinesterase, amyloid, antioxidant, benzoquinones, tau hyperphosphorylation

Contributor Information

Maria Laura Bolognesi, Email: marialaura.bolognesi@unibo.it.

Andrea Cavalli, Email: andrea.cavalli@unibo.it.

References

  • 1.Brookmeyer RS, Johnson E, Ziegler-Graham K, Arrighi HM. Forecasting the global burden of Alzheimer’s disease. Alzheimer Dementia. 2007;3:186–191. doi: 10.1016/j.jalz.2007.04.381. [DOI] [PubMed] [Google Scholar]
  • 2.Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, et al. Global prevalence of dementia: a Delphi consensus study. Lancet. 2005;366:2112–2117. doi: 10.1016/S0140-6736(05)67889-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Small DH. Acetylcholinesterase inhibitors for the treatment of dementia in Alzheimer’s disease: do we need new inhibitors? Expert Opin Emerg Drugs. 2005;10:817–825. doi: 10.1517/14728214.10.4.817. [DOI] [PubMed] [Google Scholar]
  • 4.Roberson ED, Mucke L. 100 years and counting: prospects for defeating Alzheimer’s disease. Science. 2006;314:781–784. doi: 10.1126/science.1132813. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 2002;297:353–356. doi: 10.1126/science.1072994. [DOI] [PubMed] [Google Scholar]
  • 6.Golde TE. Disease modifying therapy for AD? J Neurochem. 2006;99:689–707. doi: 10.1111/j.1471-4159.2006.04211.x. [DOI] [PubMed] [Google Scholar]
  • 7.Small DH, Mok SS, Bomstein JC. Alzheimer’s disease and Abeta toxicity: from top to bottom. Nat Rev Neurosci. 2001;2:595–598. doi: 10.1038/35086072. [DOI] [PubMed] [Google Scholar]
  • 8.Frantz S. Drug discovery: playing dirty. Nature. 2005;437:942–943. doi: 10.1038/437942a. [DOI] [PubMed] [Google Scholar]
  • 9.Iqbal K, Grundke-Iqbal I. Alzheimer disease is multifactorial and heterogeneous. Neurobiol Aging. 2000;21:901–902. doi: 10.1016/S0197-4580(00)00191-3. [DOI] [PubMed] [Google Scholar]
  • 10.Morphy R, Rankovic Z. Designed multiple ligands. An emerging drug discovery paradigm. J Med Chem. 2005;48:6523–6543. doi: 10.1021/jm058225d. [DOI] [PubMed] [Google Scholar]
  • 11.Fallow MR. Utilizing combination therapy in the treatment of Alzheimer’s disease. Expert Rev Neurother. 2004;4:799–808. doi: 10.1586/14737175.4.5.799. [DOI] [PubMed] [Google Scholar]
  • 12.Farlow MR, Miller ML, Pejovic V. Treatment options in Alzheimer’s disease: maximizing benefit, managing expectations. Dement Geriatr Cogn Disord. 2008;25:408–422. doi: 10.1159/000122962. [DOI] [PubMed] [Google Scholar]
  • 13.Toews ML, Bylund DB. Pharmacologic principles for combination therapy. Proc Am Thorac Soc. 2005;2:282–289. doi: 10.1513/pats.200504-037SR. [DOI] [PubMed] [Google Scholar]
  • 14.Cavalli A, Bolognesi ML, Minarini A, Rosini M, Tumiatti V, Recanatini M, et al. Multi-target-directed ligands to combat neurodegenerative diseases. J Med Chem. 2008;51:347–372. doi: 10.1021/jm7009364. [DOI] [PubMed] [Google Scholar]
  • 15.Small G, Dubois B. A review of compliance to treatment in Alzheimer’s disease: potential benefits of a transdermal patch. Curr Med Res Opin. 2007;23:2705–2713. doi: 10.1185/030079907X233403. [DOI] [PubMed] [Google Scholar]
  • 16.Van der Schyf CJ, Mandel S, Geldenhuys WJ, Amit T, Avramovich Y, Zheng H, et al. Novel multifunctional anti-Alzheimer drugs with various CNS neurotransmitter targets and neuroprotective moieties. Curr Alzheimer Res. 2007;4:522–536. doi: 10.2174/156720507783018226. [DOI] [PubMed] [Google Scholar]
  • 17.Melchiorre C, Andrisano V, Bolognesi ML, Budriesi R, Cavalli A, Cavrini V, et al. Acetylcholinesterase noncovalent inhibitors based on a polyamine backbone for potential use against Alzheimer’s disease. J Med Chem. 1998;41:4186–4189. doi: 10.1021/jm9810452. [DOI] [PubMed] [Google Scholar]
  • 18.Doods HN, Quirion R, Mihm G, Engel W, Rudolf K, Entzeroth M, et al. Therapeutic potential of CNS-active M2 antagonists: novel structures and pharmacology. Life Sci. 1993;52:497–503. doi: 10.1016/0024-3205(93)90307-O. [DOI] [PubMed] [Google Scholar]
  • 19.Munoz-Torrero D, Camps P. Dimeric and hybrid anti-Alzheimer drug candidates. Curr Med Chem. 2006;13:399–422. doi: 10.2174/092986706775527974. [DOI] [PubMed] [Google Scholar]
  • 20.Alvarez A, Alarcon R, Opazo C, Campos EO, Munoz FJ, Calderon FH, et al. Stable complexes involving acetylcholinesterase and amyloid-beta peptide change the biochemical properties of the enzyme and increase the neurotoxicity of Alzheimer’s fibrils. J Neurosci. 1998;18:3213–3223. doi: 10.1523/JNEUROSCI.18-09-03213.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Campos EO, Alvarez A, Inestrosa NC. Brain acetylcholinesterase promotes amyloid-beta-peptide aggregation but does not hydrolyze amyloid precursor protein peptides. Neurochem Res. 1998;23:135–140. doi: 10.1023/A:1022416505725. [DOI] [PubMed] [Google Scholar]
  • 22.Inestrosa NC, Alvarez A, Perez CA, Moreno RD, Vicente M, Linker C, et al. Acetylcholinesterase accelerates assembly of amyloid-beta-peptides into Alzheimer’s fibrils: possible role of the peripheral site of the enzyme. Neuron. 1996;16:881–891. doi: 10.1016/S0896-6273(00)80108-7. [DOI] [PubMed] [Google Scholar]
  • 23.Bourne Y, Taylor P, Bougis PE, Marchot P. Crystal structure of mouse acetylcholinesterase. A peripheral site-occluding loop in a tetrameric assembly. J Biol Chem. 1999;274:2963–2970. doi: 10.1074/jbc.274.5.2963. [DOI] [PubMed] [Google Scholar]
  • 24.Castro A, Martinez A. Peripheral and dual binding site acetylcholinesterase inhibitors: implications in treatment of Alzheimer’s disease. Mini Rev Med Chem. 2001;1:267–272. doi: 10.2174/1389557013406864. [DOI] [PubMed] [Google Scholar]
  • 25.Recanatini M, Valenti P. Acetylcholinesterase inhibitors as a starting point towards improved Alzheimer’s disease therapeutics. Curr Pharm Des. 2004;10:3157–3166. doi: 10.2174/1381612043383313. [DOI] [PubMed] [Google Scholar]
  • 26.Castro A, Martinez A. Targeting Beta-amyloid pathogenesis through acetylcholinesterase inhibitors. Curr Pharm Des. 2006;12:4377–4387. doi: 10.2174/138161206778792985. [DOI] [PubMed] [Google Scholar]
  • 27.Melchiorre C, Antonello A, Banzi R, Bolognesi ML, Minarini A, Rosini M, et al. Polymethylene tetraamine backbone as template for the development of biologically active polyamines. Med Res Rev. 2003;23:200–233. doi: 10.1002/med.10029. [DOI] [PubMed] [Google Scholar]
  • 28.Bolognesi ML, Minarini A, Rosini M, Tumiatti V, Melchiorre C. From dual binding site acetylcholinesterase inhibitors to multi-target-directed ligands (MTDLs): a step forward in the treatment of Alzheimer’s disease. Mini Rev Med Chem. 2008;8:960–967. doi: 10.2174/138955708785740652. [DOI] [PubMed] [Google Scholar]
  • 29.Gutzmann H, Hadler D. Sustained efficacy and safety of idebenone in the treatment of Alzheimer’s disease: update on a 2-year double-blind multicentre study. J Neural Transm Suppl. 1998;54:301–310. doi: 10.1007/978-3-7091-7508-8_30. [DOI] [PubMed] [Google Scholar]
  • 30.Hirai K, Hayako H, Kato K, Miyamoto M. Idebenone protects hippocampal neurons against amyloid beta-peptide-induced neurotoxicity in rat primary cultures. Naunyn Schmiedebergs Arch Pharmacol. 1998;358:582–585. doi: 10.1007/PL00005296. [DOI] [PubMed] [Google Scholar]
  • 31.Moreira PI, Santos MS, Oliveira CR. Alzheimer’s disease: a lesson from mitochondrial dysfunction. Antioxid Redox Signal. 2007;9:1621–1630. doi: 10.1089/ars.2007.1703. [DOI] [PubMed] [Google Scholar]
  • 32.Adkins JC, Noble S. Idebenone: a review of its use in mild to moderate Alzheimer’s disease. CNS Drugs. 1998;9:403–419. doi: 10.2165/00023210-199809050-00006. [DOI] [Google Scholar]
  • 33.Cavalli A, Bolognesi ML, Capsoni S, Andrisano V, Bartolini M, Margotti E, et al. A small molecule targeting the multifactorial nature of Alzheimer’s disease. Angew Chem Int Ed Engl. 2007;46:3689–3692. doi: 10.1002/anie.200700256. [DOI] [PubMed] [Google Scholar]
  • 34.Nesterov EE, Skoch J, Hyman BT, Klunk WE, Bacskai BJ, Swager TM. In vivo optical imaging of amyloid aggregates in brain: design of fluorescent markers. Angew Chem Int Ed Engl. 2005;44:5452–5456. doi: 10.1002/anie.200500845. [DOI] [PubMed] [Google Scholar]
  • 35.Bolognesi ML, Banzi R, Minarini A, Melchiorre C, inventors. Process for preparation of 1,4-benzoquinone-2,5-diamines by reaction of amines with 1,4-benzoquinones bearing leaving groups at the 2- and 5-positions. PCT Int Appl WO 2006134457.
  • 36.Bolognesi ML, Banzi R, Bartolini M, Cavalli A, Tarozzi A, Andrisano V, et al. Novel class of quinone-bearing polyamines as multi-target-directed ligands to combat Alzheimer’s disease. J Med Chem. 2007;50:4882–4897. doi: 10.1021/jm070559a. [DOI] [PubMed] [Google Scholar]
  • 37.Andrisano V, Bartolini M, Bolognesi ML, Cavalli A, Melchiorre C, Recanatini M, inventors. Preparation of 2,5-bis-diamine-[1,4]benzoquinone derivatives for the treatment of Alzheimer’s disease and a process for their preparation and intermediates therefor. PCT Int Appl WO 2003087035.
  • 38.Mordente A, Martorana GE, Minotti G, Giardina B. Antioxidant properties of 2,3-dimethoxy-5-methyl-6-(10-hydroxydecyl)-1,4-benzoquinone (idebenone) Chem Res Toxicol. 1998;11:54–63. doi: 10.1021/tx970136j. [DOI] [PubMed] [Google Scholar]
  • 39.Raina AK, Templeton DJ, Deak JC, Perry G, Smith MA. Quinone reductase (NQO1), a sensitive redox indicator, is increased in Alzheimer’s disease. Redox Rep. 1999;4:23–27. doi: 10.1179/135100099101534701. [DOI] [PubMed] [Google Scholar]
  • 40.Moreira PI, Siedlak SL, Aliev G, Zhu X, Cash AD, Smith MA, et al. Oxidative stress mechanisms and potential therapeutics in Alzheimer disease. J Neural Transm. 2005;112:921–932. doi: 10.1007/s00702-004-0242-8. [DOI] [PubMed] [Google Scholar]
  • 41.SantaCruz KS, Yazlovitskaya E, Collins J, Johnson J, DeCarli C. Regional NAD(P)H:quinone oxidoreductase activity in Alzheimer’s disease. Neurobiol Aging. 2004;25:63–69. doi: 10.1016/S0197-4580(03)00117-9. [DOI] [PubMed] [Google Scholar]
  • 42.Kang YH, Pezzuto JM. Induction of quinone reductase as a primary screen for natural product anticarcinogens. Methods Enzymol. 2004;382:380–414. doi: 10.1016/S0076-6879(04)82021-4. [DOI] [PubMed] [Google Scholar]
  • 43.Shen L, Ji HF, Zhang HY. How to understand the dichotomy of antioxidants. Biochem Biophys Res Commun. 2007;362:543–545. doi: 10.1016/j.bbrc.2007.07.125. [DOI] [PubMed] [Google Scholar]
  • 44.Bartolini M, Bertucci C, Cavrini V, Andrisano V. Beta-Amyloid aggregation induced by human acetylcholinesterase: inhibition studies. Biochem Pharmacol. 2003;65:407–416. doi: 10.1016/S0006-2952(02)01514-9. [DOI] [PubMed] [Google Scholar]
  • 45.Alvarez A, Opazo C, Alarcon R, Garrido J, Inestrosa NC. Acetylcholinesterase promotes the aggregation of amyloid-beta-peptide fragments by forming a complex with the growing fibrils. J Mol Biol. 1997;272:348–361. doi: 10.1006/jmbi.1997.1245. [DOI] [PubMed] [Google Scholar]
  • 46.Bolognesi ML, Andrisano V, Bartolini M, Banzi R, Melchiorre C. Propidium-based polyamine ligands as potent inhibitors of acetylcholinesterase and acetylcholinesterase-induced amyloid-beta aggregation. J Med Chem. 2005;48:24–27. doi: 10.1021/jm049156q. [DOI] [PubMed] [Google Scholar]
  • 47.Piazzi L, Rampa A, Bisi A, Gobbi S, Belluti F, Cavalli A, et al. 3-(4-[[Benzyl(methyl)amino]methyl]phenyl)-6,7-dimethoxy-2H-2-chromenone (AP2238) inhibits both acetylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation: a dual function lead for Alzheimer’s disease therapy. J Med Chem. 2003;46:2279–2282. doi: 10.1021/jm0340602. [DOI] [PubMed] [Google Scholar]
  • 48.Dickerson TJ, Beuscher AE, Rogers CJ, Hixon MS, Yamamoto N, Xu Y, et al. Discovery of acetylcholinesterase peripheral anionic site ligands through computational refinement of a directed library. Biochemistry. 2005;44:14845–14853. doi: 10.1021/bi051613x. [DOI] [PubMed] [Google Scholar]
  • 49.Munoz-Ruiz P, Rubio L, Garcia-Palomero E, Dorronsoro I, del Monte-Millan M, Valenzuela R, et al. Design, synthesis, and biological evaluation of dual binding site acetylcholinesterase inhibitors: new disease-modifying agents for Alzheimer’s disease. J Med Chem. 2005;48:7223–7233. doi: 10.1021/jm0503289. [DOI] [PubMed] [Google Scholar]
  • 50.Xie Q, Wang H, Xia Z, Lu M, Zhang W, Wang X, et al. Bis-(−)-nor-meptazinols as novel nanomolar cholinesterase inhibitors with high inhibitory potency on amyloid-beta aggregation. J Med Chem. 2008;51:2027–2036. doi: 10.1021/jm070154q. [DOI] [PubMed] [Google Scholar]
  • 51.Camps P, Formosa X, Galdeano C, Gomez T, Munoz-Torrero D, Scarpellini M, et al. Novel donepezil-based inhibitors of acetyl- and butyrylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation. J Med Chem. 2008;51:3588–3598. doi: 10.1021/jm8001313. [DOI] [PubMed] [Google Scholar]
  • 52.Rees TM, Brimijoin S. The role of acetylcholinesterase in the pathogenesis of Alzheimer’s disease. Drugs Today (Barc) 2003;39:75–83. doi: 10.1358/dot.2003.39.1.740206. [DOI] [PubMed] [Google Scholar]
  • 53.Ono K, Hasegawa K, Naiki H, Yamada M. Reformed beta-amyloid fibrils are destabilized by coenzyme Q10 in vitro. Biochem Biophys Res Commun. 2005;330:111–116. doi: 10.1016/j.bbrc.2005.02.132. [DOI] [PubMed] [Google Scholar]
  • 54.Tomiyama T, Shoji A, Kataoka K, Suwa Y, Asano S, Kaneko H, et al. Inhibition of amyloid beta protein aggregation and neurotoxicity by rifampicin. Its possible function as a hydroxyl radical scavenger. J Biol Chem. 1996;271:6839–6844. doi: 10.1074/jbc.271.12.6839. [DOI] [PubMed] [Google Scholar]
  • 55.Bartolini M, Bertucci C, Bolognesi ML, Cavalli A, Melchiorre C, Andrisano V. Insight into the kinetic of amyloid beta (1–42) peptide self-aggregation: elucidation of inhibitors’ mechanism of action. Chembiochem. 2007;8:2152–2161. doi: 10.1002/cbic.200700427. [DOI] [PubMed] [Google Scholar]
  • 56.Forloni G, Colombo L, Girola L, Tagliavini F, Salmona M. Anti-amyloidogenic activity of tetracyclines: studies in vitro. FEBS Lett. 2001;487:404–407. doi: 10.1016/S0014-5793(00)02380-2. [DOI] [PubMed] [Google Scholar]
  • 57.Dewachter I, Van Leuven F. Secretases as targets for the treatment of Alzheimer’s disease: the prospects. Lancet Neurol. 2002;1:409–416. doi: 10.1016/S1474-4422(02)00188-6. [DOI] [PubMed] [Google Scholar]
  • 58.Melnikova I. Therapies for Alzheimer’s disease. Nat Rev Drug Discov. 2007;6:341–342. doi: 10.1038/nrd2314. [DOI] [PubMed] [Google Scholar]
  • 59.Capsoni S, Ugolini G, Comparini A, Ruberti F, Berardi N, Cattaneo A. Alzheimer-like neurodegeneration in aged antinerve growth factor transgenic mice. Proc Natl Acad Sci U S A. 2000;97:6826–6831. doi: 10.1073/pnas.97.12.6826. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Capsoni S, Cattaneo A. On the molecular basis linking Nerve Growth Factor (NGF) to Alzheimer’s disease. Cell Mol Neurobiol. 2006;26:619–633. doi: 10.1007/s10571-006-9112-2. [DOI] [PubMed] [Google Scholar]
  • 61.Capsoni S, Giannotta S, Cattaneo A. Beta-amyloid plaques in a model for sporadic Alzheimer’s disease based on transgenic anti-nerve growth factor antibodies. Mol Cell Neurosci. 2002;21:15–28. doi: 10.1006/mcne.2002.1163. [DOI] [PubMed] [Google Scholar]
  • 62.Capsoni S, Andrisano V, Bartolini M, Bolognesi ML, Cavalli A, Margotti E, et al. S4-04-04 Memoquin, a novel multifunctional compound for Alzheimer’s disease: An up-date on preclinical studies. Alzheimer Dementia. 2006;2(Suppl 1):S73–S74. doi: 10.1016/j.jalz.2006.05.287. [DOI] [Google Scholar]
  • 63.Liu K, Xu L, Szalkowski D, Li Z, Ding V, Kwei G, et al. Discovery of a potent, highly selective, and orally efficacious small-molecule activator of the insulin receptor. J Med Chem. 2000;43:3487–3494. doi: 10.1021/jm000285q. [DOI] [PubMed] [Google Scholar]
  • 64.Wang Y, Santa-Cruz K, DeCarli C, Johnson JA. NAD(P)H:quinone oxidoreductase activity is increased in hippocampal pyramidal neurons of patients with Alzheimer’s disease. Neurobiol Aging. 2000;21:525–531. doi: 10.1016/S0197-4580(00)00114-7. [DOI] [PubMed] [Google Scholar]
  • 65.Azzi A. Oxidative stress: A dead end or a laboratory hypothesis? Biochem Biophys Res Commun. 2007;362:230–232. doi: 10.1016/j.bbrc.2007.07.124. [DOI] [PubMed] [Google Scholar]

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