Structure–Activity Relationships and Computational Investigations into the Development of Potent and Balanced Dual-Acting Butyrylcholinesterase Inhibitors and Human Cannabinoid Receptor 2 Ligands with Pro-Cognitive in Vivo Profiles
Abstract
The enzyme butyrylcholinesterase (BChE) and the human cannabinoid receptor 2 ( h CB 2 R) represent promising targets for pharmacotherapy in the later stages of Alzheimer’s disease. We merged pharmacophores for both targets into small benzimidazole-based molecules, investigated SARs, and identified several dual-acting ligands with a balanced affinity/inhibitory activity and an excellent selectivity over both h CB 1 R and h AChE. A homology model for the h CB 2 R was developed based on the h CB 1 R crystal structure and used for molecular dynamics studies to investigate binding modes. In vitro studies proved h CB 2 R agonism. Unwanted μ-opioid receptor affinity could be designed out. One well-balanced dual-acting and selective h BChE inhibitor/ h CB 2 R agonist showed superior in vivo activity over the lead CB 2 agonist with regards to cognition improvement. The data shows the possibility to combine a small molecule with selective and balanced GPCR-activity/enzyme inhibition and in vivo activity for the therapy of AD and may help to rationalize the development of other dual-acting ligands.
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The tacrine-cannabinoid hybrids show higher inhibition of ChE compared with tacrine (16) in vitro.
“Overall, in vitro assays showed higher inhibition of ChE by the hybrids compared with 16.”
From From combinations to multitarget-directed ligands: A continuum in Alzheimer’s disease polypharmacology (2021) · cites this paper as [131]
All tested tacrine-cannabinoid hybrids reduce Aβ aggregation, unlike tacrine (16).
“Different from 16, all the tested hybrids showed effect in reducing Aβ aggregation.”
From From combinations to multitarget-directed ligands: A continuum in Alzheimer’s disease polypharmacology (2021) · cites this paper as [131]
The tacrine-cannabinoid hybrids display an immunomodulatory effect similar to the parent hCB2R agonist (43), despite lower hCB2R affinity.
“Conversely, despite the significantly lower hCB2R affinity compared with 43, the hybrids displayed an immunomodulatory effect similar to the parent molecule (43).”
From From combinations to multitarget-directed ligands: A continuum in Alzheimer’s disease polypharmacology (2021) · cites this paper as [131]
The tested tacrine-cannabinoid hybrids have significantly higher in vivo efficacy at 0.1 mg/kg than the parent molecules tacrine (16) and the hCB2R agonist (43).
“Eventually, in vivo efficacy of the tested hybrids resulted significantly higher (0.1 mg/kg), than for the parent molecules 16 and 43.”
From From combinations to multitarget-directed ligands: A continuum in Alzheimer’s disease polypharmacology (2021) · cites this paper as [131]
Cites
1 retracted
RETRACTED ARTICLE: Crystal structures of agonist-bound human cannabinoid receptor CB1
Hua, T., Vemuri, K. V., Nikas, S. P., Laprairie, R. B., Wu, Y., Qu, L., Pu, M., Korde, A., Jiang, S. H., Ho, J., et al. (2017) · Nature · doi:10.1038/nature23272 · Cited by 484 · see citing works
RetractedLipinski, C. A., Lombardo, F., Dominy, B. W., & Feeney, P. J. (1997) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(96)00423-1 · Cited by 11,484 · see citing works
Structure of a cannabinoid receptor and functional expression of the cloned cDNA
Matsuda, L. A., Lolait, S. J., Brownstein, M. J., Young, A. C., & Bonner, T. I. (1990) · Nature · doi:10.1038/346561a0 · Cited by 5,011 · see citing works
NMR Chemical Shifts of Common Laboratory Solvents as Trace Impurities
Gottlieb, H. E., Kotlyar, V., & Nudelman, A. (1997) · The Journal of Organic Chemistry · doi:10.1021/jo971176v · Cited by 3,754 · see citing works
SELECTIVE LOSS OF CENTRAL CHOLINERGIC NEURONS IN ALZHEIMER'S DISEASE
DAVIES, P. (1976) · The Lancet · doi:10.1016/s0140-6736(76)91936-x · Cited by 3,565 · see citing works
Ballesteros, J. A., & Weinstein, H. (1995) · Methods in neurosciences · doi:10.1016/s1043-9471(05)80049-7 · Cited by 3,001 · see citing works
International Union of Pharmacology. XXVII. Classification of Cannabinoid Receptors
Howlett, A. C., Barth, F., Bonner, T. I., Cabral, G., Casellas, P., Devane, W. A., Felder, C. C., Herkenham, M., Mackie, K., Martin, B. R., et al. (2002) · Pharmacological Reviews · doi:10.1124/pr.54.2.161 · Cited by 2,819 · see citing works
Ballard, C., Gauthier, S., Corbett, A., Brayne, C., Aarsland, D., & Jones, E. (2011) · The Lancet · doi:10.1016/s0140-6736(10)61349-9 · Cited by 2,336 · see citing works
Microglia in neurodegenerative disease
Perry, V. H., Nicoll, J. A. R., & Holmes, C. (2010) · Nature Reviews Neurology · doi:10.1038/nrneurol.2010.17 · Cited by 1,543 · see citing works
Identification and Functional Characterization of Brainstem Cannabinoid CB<sub>2</sub>Receptors
Van Sickle, M. D., Duncan, M., Kingsley, P. J., Mouihate, A., Urbani, P., Mackie, K., Stella, N., Makriyannis, A., Piomelli, D., Davison, J. S., et al. (2005) · Science · doi:10.1126/science.1115740 · Cited by 1,470 · see citing works
Wyss-Coray (2006) · doi:10.1038/nm1484 · Cited by 1,284 · see citing works
Designed Multiple Ligands. An Emerging Drug Discovery Paradigm
Morphy, R., & Ranković, Z. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm058225d · Cited by 1,237 · see citing works
Neurobiology of butyrylcholinesterase
Darvesh, S., Hopkins, D. A., & Geula, C. (2003) · Nature reviews. Neuroscience · doi:10.1038/nrn1035 · Cited by 896 · see citing works
(2016) · London School of Economics and Political Science Research Online (London School of Economics and Political Science) · Cited by 874 · see citing works
Greig, N. H., Utsuki, T., Ingram, D. K., Wang, Y., Pepeu, G., Scali, C., Yu, Q.-S., Mamczarz, J., Holloway, H. W., Giordano, T., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0508575102 · Cited by 745 · see citing works
Maurice, T., Lockhart, B. P., & Privat, A. (1996) · Brain Research · doi:10.1016/0006-8993(95)01032-7 · Cited by 524 · see citing works
Self-citationRoss, R. A., Brockie, H. C., Stevenson, L., Murphy, V. L., Templeton, F., Makriyannis, A., & Pertwee, R. G. (1999) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0702351 · Cited by 407 · see citing works
Stimulation of cannabinoid receptor 2 (CB2) suppresses microglial activation
Ehrhart, J. C., Obregon, D. F., Mori, T., Hou, H., Sun, N., Bai, Y., Klein, T., Fernandez, F., Tan, J., & Shytle, R. D. (2005) · Journal of Neuroinflammation · doi:10.1186/1742-2094-2-29 · Cited by 379 · see citing works
Cannabinoid CB2 receptor: a new target for controlling neural cell survival?
Fernández‐Ruíz, J., Romero, J., Velasco, G., Tolón, R. M., Ramos, J. A., & Guzmán, M. (2006) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2006.11.001 · Cited by 362 · see citing works
Núñez, E., Benito, C., Pazos, M. R., Barbáchano, A., Fajardo, O., González, S. R., Tolón, R. M., & Romero, J. (2004) · Synapse · doi:10.1002/syn.20050 · Cited by 334 · see citing works
Li, Q., Yang, H., Chen, Y., & Sun, H. (2017) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2017.03.062 · Cited by 331 · see citing works
A review of butyrylcholinesterase as a therapeutic target in the treatment of Alzheimer’s disease
Nordberg, A., Ballard, C., Bullock, R., Darreh-Shori, T., & Somogyi, M. (2013) · The Primary Care Companion For CNS Disorders · doi:10.4088/pcc.12r01412 · Cited by 323 · see citing works
Butyrylcholinesterase in the life cycle of amyloid plaques
Guillozet-Bongaarts, A. L., Mesulam, M. M., Smiley, J. F., & Mash, D. C. (1997) · Annals of Neurology · doi:10.1002/ana.410420613 · Cited by 312 · see citing works
Butyrylcholinesterase reactivity differentiates the amyloid plaques of aging from those of dementia
Mesulam, M. M., & Geula, C. (1994) · Annals of Neurology · doi:10.1002/ana.410360506 · Cited by 259 · see citing works
Martín-Moreno, A. M., Brera, B., Spuch, C., Carro, E., García‐García, L., Delgado, M., Pozo, M. A., Innamorato, N. G., Cuadrado, A., & CEBALLOS, M. L. D. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-8 · Cited by 246 · see citing works
Sheng, W. S., Hu, S., Min, X. M., Cabral, G. A., Lokensgard, J. R., & Peterson, P. K. (2004) · Glia · doi:10.1002/glia.20108 · Cited by 246 · see citing works
Alas, S., & Bonavida, B. (2003) · PubMed · Cited by 240 · see citing works
Wright, C. I., Geula, C., & Mesulam, M.-M. (1993) · Annals of Neurology · doi:10.1002/ana.410340312 · Cited by 237 · see citing works
CB2 receptor and amyloid pathology in frontal cortex of Alzheimer's disease patients
Solas, M., Francis, P. T., Franco, R., & Ramírez, M. J. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.06.005 · Cited by 209 · see citing works
Lange, J. H. M., van Stuivenberg, H. H., Coolen, H. K. A. C., et al. (2004) · Journal of Medicinal Chemistry · doi:10.1021/jm040843r · Cited by 181 · see citing works
Development of an in-vivo active reversible butyrylcholinesterase inhibitor
Košak, U., Brus, B., Knez, D., Šink, R., Žakelj, S., Trontelj, J., Pišlar, A. H., Šlenc, J., Gobec, M., Živin, M., et al. (2016) · Scientific Reports · doi:10.1038/srep39495 · Cited by 176 · see citing works
Activation of the CB2 receptor system reverses amyloid-induced memory deficiency
Wu, J., Bie, B., Yang, H., Xu, J. J., Brown, D. L., & Naguib, M. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.06.011 · Cited by 174 · see citing works
Ferrer, I. (2012) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2012.03.005 · Cited by 174 · see citing works
cAMP detection methods in HTS: selecting the best from the rest
Williams, C. (2004) · Nature Reviews Drug Discovery · doi:10.1038/nrd1306 · Cited by 170 · see citing works
Lahmy, V., Meunier, J., Malmström, S., Naert, G., Givalois, L., Kim, S. H., Villard, V., Vamvakides, A., & Maurice, T. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2013.70 · Cited by 163 · see citing works
Self-citationEndocannabinoid signalling in innate and adaptive immunity
Chiurchiù, V., Battistini, L., & Maccarrone, M. (2015) · Immunology · doi:10.1111/imm.12441 · Cited by 158 · see citing works
Nepovimová, E., Uliassi, E., Korábečný, J., Peña‐Altamira, E., Samez, S., Pesaresi, A., Garcia, G. E., Bartolini, M., Andrisano, V., Bergamini, C., et al. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm5010804 · Cited by 154 · see citing works
Molina‐Holgado, F., Molina‐Holgado, E., Guaza, C., & Rothwell, N. J. (2002) · Journal of Neuroscience Research · doi:10.1002/jnr.10165 · Cited by 148 · see citing works
A new efficient synthesis of isothiocyanates from amines using di-tert-butyl dicarbonate
Munch, H. K., Hansen, J. S., Pittelkow, M., Christensen, J. B., & Boas, U. (2008) · Tetrahedron Letters · doi:10.1016/j.tetlet.2008.03.045 · Cited by 147 · see citing works
Yao, B. B., Hsieh, G. C., Frost, J. M., Fan, Y., Garrison, T. R., Daza, A. V., Grayson, G. K., Zhu, C. Z., Pai, M., Chandran, P., et al. (2008) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0707568 · Cited by 140 · see citing works
Emerging Role of High-Mobility Group Box 1 (HMGB1) in Liver Diseases
Chen, R., Hou, W., Zhang, Q., Kang, R., Fan, X., & Tang, D. (2013) · Molecular Medicine · doi:10.2119/molmed.2013.00099 · Cited by 130 · see citing works
Nepovimová, E., Korábečný, J., Doležal, R., Babkova, K., Ondřejíček, A., Jun, D., Šepsová, V., Horova, A., Hrabinová, M., Soukup, O., et al. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01325 · Cited by 129 · see citing works
Reporter-gene systems for the study of G-protein-coupled receptors
Hill, S. J. (2001) · Current Opinion in Pharmacology · doi:10.1016/s1471-4892(01)00091-1 · Cited by 123 · see citing works
Marker proteins for gene expression
Wood, K. V. (1995) · Current Opinion in Biotechnology · doi:10.1016/0958-1669(95)80009-3 · Cited by 116 · see citing works
Sawatzky, E., Wehle, S., Kling, B., Wendrich, J., Bringmann, G., Sotriffer, C., Heilmann, J., & Decker, M. W. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01674 · Cited by 103 · see citing works
Self-citationMontanari, S., Scalvini, L., Bartolini, M., Belluti, F., Gobbi, S., Andrisano, V., Ligresti, A., Marzo, V. D., Rivara, S., Mor, M., et al. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b00609 · Cited by 87 · see citing works
Multitarget Tacrine Hybrids with Neuroprotective Properties to Confront Alzheimer’s Disease
Špilovská, K., Korábečný, J., Nepovimová, E., Doležal, R., Mezeiová, E., Soukup, O., & Kuča, K. (2016) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026605666160927152728 · Cited by 86 · see citing works
Naour, M. L., Akgün, E., Yekkirala, A. S., Lunzer, M. M., Powers, M. D., Kalyuzhny, A. E., & Portoghese, P. S. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm4005219 · Cited by 85 · see citing works
Dual Targeting of Adenosine A2A Receptors and Monoamine Oxidase B by 4H-3,1-Benzothiazin-4-ones
Stößel, A., Schlenk, M., Hinz, S., et al. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm400336x · Cited by 85 · see citing works
Darras, F. H., Pockes, S., Huang, G., Wehle, S., Straßer, A., Wittmann, H., Nimczick, M., Sotriffer, C., & Decker, M. W. (2014) · ACS Chemical Neuroscience · doi:10.1021/cn4002126 · Cited by 80 · see citing works
Self-citationMaurice, T., Strehaïano, M., Siméon, N., Bertrand‐Gaday, C., & Chatonnet, A. (2015) · Behavioural Brain Research · doi:10.1016/j.bbr.2015.08.026 · Cited by 73 · see citing works
Self-citationType-2 cannabinoid receptors in neurodegeneration
Bisogno, T., Oddi, S., Piccoli, A., Fazio, D., & Maccarrone, M. (2016) · Pharmacological Research · doi:10.1016/j.phrs.2016.07.021 · Cited by 71 · see citing works
Hunger, A., Kebrle, J., Rossi, A., & Hoffmann, K. J. (1960) · Helvetica Chimica Acta · doi:10.1002/hlca.19600430412 · Cited by 70 · see citing works
Novel benzimidazole derivatives as selective CB2 agonists
Pagé, D., Balaux, É., Boisvert, L., Liu, Z., Milburn, C., Tremblay, M., Wei, Z., Woo, S., Luo, X., Cheng, Y., et al. (2008) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2008.05.073 · Cited by 66 · see citing works
Lange, J. H. M., Coolen, H. K. A. C., van der Neut, M. A. W., Borst, A. J. M., Stork, B., Verveer, P. C., & Kruse, C. G. (2010) · Journal of Medicinal Chemistry · doi:10.1021/jm901614b · Cited by 61 · see citing works
Comparison Analysis of Gene Expression Patterns between Sporadic Alzheimer's and Parkinson's Disease
Grünblatt, E., Zander, N., Bartl, J., Li, J., Monoranu, C., Arzberger, T., Ravid, R., Roggendorf, W., Gerlach, M., & Riederer, P. F. (2007) · Journal of Alzheimer s Disease · doi:10.3233/jad-2007-12402 · Cited by 59 · see citing works
Darras, F. H., Wehle, S., Huang, G., Sotriffer, C., & Decker, M. W. (2014) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2014.06.045 · Cited by 58 · see citing works
Self-citationWaeber, G., Thompson, N. A., Chautard, T., Steinmann, M., NICOD, P. H., Pralong, F. P., Calandra, T., & Gaillard, R. C. (1998) · Molecular Endocrinology · doi:10.1210/mend.12.5.0109 · Cited by 58 · see citing works
Igel, P., Geyer, R., Straßer, A., et al. (2009) · Journal of Medicinal Chemistry · doi:10.1021/jm900526h · Cited by 57 · see citing works
Role of Myeloma-Derived MIF in Myeloma Cell Adhesion to Bone Marrow and Chemotherapy Response
Zheng, Y., Wang, Q., Li, T., et al. (2016) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djw131 · Cited by 56 · see citing works
González-Naranjo, P., Pérez-Macías, N., Campillo, N. E., et al. (2013) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2013.11.026 · Cited by 50 · see citing works
Pharmacological Profile of Histaprodifens at Four Recombinant Histamine H1 Receptor Species Isoforms
Straßer, A., Striegl, B., Wittmann, H., et al. (2007) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.107.129601 · Cited by 45 · see citing works
Self-citationSadek, B. S., Khan, N., Darras, F. H., Pockes, S., & Decker, M. W. (2016) · Physiology & Behavior · doi:10.1016/j.physbeh.2016.08.022 · Cited by 42 · see citing works
Self-citationKato, K., Nomoto, M., Izumi, H., Ise, T., Nakano, S., Niho, Y., & Kohno, K. (2000) · Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression · doi:10.1016/s0167-4781(00)00168-8 · Cited by 40 · see citing works
Khan, N., Saad, A. K., Nurulain, S. M., Darras, F. H., Decker, M. W., & Sadek, B. S. (2015) · Behavioural Brain Research · doi:10.1016/j.bbr.2015.10.022 · Cited by 40 · see citing works
Self-citationDolles, D., Nimczick, M., Scheiner, M., Ramler, J., Stadtmüller, P., Sawatzky, E., Drakopoulos, A., Sotriffer, C., Wittmann, H., Straßer, A., et al. (2015) · ChemMedChem · doi:10.1002/cmdc.201500418 · Cited by 39 · see citing works
Self-citationModulation of GPCRs by monovalent cations and anions
Straßer, A., Wittmann, H., Schneider, E. H., & Seifert, R. (2014) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-014-1073-2 · Cited by 36 · see citing works
Self-citationNeuropathology of Alzheimer's Disease and its Variants
Duyckaerts, C. J., & Dickson, D. W. (2011) · Wiley eBooks · doi:10.1002/9781444341256.ch10 · Cited by 34 · see citing works
Nimczick, M., & Decker, M. W. (2015) · ChemMedChem · doi:10.1002/cmdc.201500041 · Cited by 28 · see citing works
Self-citationPerrey, D. A., Gilmour, B. P., Thomas, B. F., et al. (2014) · ACS Medicinal Chemistry Letters · doi:10.1021/ml4004759 · Cited by 27 · see citing works
Freitag, M., Schemies, J., Larsen, T., et al. (2011) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2011.01.026 · Cited by 26 · see citing works
NOpiates: Novel Dual Action Neuronal Nitric Oxide Synthase Inhibitors with μ-Opioid Agonist Activity
Renton, P., Green, B. J., Maddaford, S. P., Rakhit, S., & Andrews, J. S. (2012) · ACS Medicinal Chemistry Letters · doi:10.1021/ml200268w · Cited by 23 · see citing works
Huang, G., Drakopoulos, A., Saedtler, M., et al. (2017) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2017.08.045 · Cited by 20 · see citing works
Sodium binding to hH3R and hH4R — a molecular modeling study
Wittmann, H., Seifert, R., & Straßer, A. (2014) · Journal of Molecular Modeling · doi:10.1007/s00894-014-2394-2 · Cited by 15 · see citing works
Self-citationDual-Acting Compounds Acting as Receptor Ligands and Enzyme Inhibitors
Dolles, D., & Decker, M. W. (2017) · Elsevier eBooks · doi:10.1016/b978-0-08-101011-2.00005-2 · Cited by 7 · see citing works
Self-citationComputational Methods in Multitarget Drug Discovery
Bottegoni, G., & Cavalli, A. (2017) · Elsevier eBooks · doi:10.1016/b978-0-08-101011-2.00009-x · Cited by 6 · see citing works
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Proschak, E., Stark, H., & Merk, D. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00760 · Cited by 498 · see citing works
Albertini, C., Salerno, A., de Sena Murteira Pinheiro, P., & Bolognesi, M. L. (2021) · Medicinal Research Reviews · doi:10.1002/med.21699 · Cited by 179 · see citing works
DARK Classics in Chemical Neuroscience: Etonitazene and Related Benzimidazoles
Ujváry, I., Christie, R., Evans-Brown, M., Gallegos, A., Jorge, R., de Morais, J., & Sedefov, R. (2021) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.1c00037 · Cited by 141 · see citing works
Hoffmann, M., Stiller, C., Endres, E., Scheiner, M., Gunesch, S., Sotriffer, C., Maurice, T., & Decker, M. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01012 · Cited by 105 · see citing works
Self-citationScheiner, M., Dolles, D., Gunesch, S., Hoffmann, M., Nabissi, M., Marinelli, O., Naldi, M., Bartolini, M., Petralla, S., Poeta, E., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b00623 · Cited by 49 · see citing works
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- Authors
- Dolles, D., Hoffmann, M., Gunesch, S., Marinelli, O., Möller, J., Santoni, G., Chatonnet, A., Lohse, M. J., Wittmann, H.-J., Strasser, A., Nabissi, M., Maurice, T., & Decker, M.
- Affiliations
- University of Würzburg (DE)
- Università di Camerino (IT)
- Institute of Pharmacology and Toxicology, Julius Maximilian University of Würzburg, Versbacher Strabe 9, D-97078 Würzburg, Germany
- Université de Montpellier (FR)
- University of Regensburg (DE)
- Inserm (FR)
- Corresponding author
- Decker, Michael
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2018-02-05
- Volume
- 61
- Issue
- 4
- Pages
- 1646-1663
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2787270055
- Cited by
- 67
- References
- 76
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 8 · 2023: 6 · 2022: 7 · 2021: 9 · 2020: 12 · 2019: 12 · 2018: 5
- FWCI
- 7.74
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
- Unicam Scientific Publications (University of Camerino) (submittedVersion)
- Funders
- Deutscher Akademischer Austauschdienst (57396178)
- Bayerisches Staatsministerium f?r Bildung und Kultus, Wissenschaft und Kunst
- Deutsche Forschungsgemeinschaft (DE/1546/6-3)
- Studienstiftung des Deutschen Volkes
- Topics
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- butyrylcholinesterase inhibitors, cannabinoid receptor 2 agonist, Alzheimer's disease, benzimidazole derivatives, structure-activity relationship, pharmacophore design, homology modeling, molecular dynamics, binding mode, mu-opioid receptor selectivity, cognitive enhancement
- MeSH terms
- Alzheimer Disease, Benzimidazoles, Butyrylcholinesterase, Cognition, Enzyme Inhibitors, Humans, Ligands, Protein Binding, Structure-Activity Relationship, Receptors, G-Protein-Coupled, Receptor, Cannabinoid, CB2
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