茚酮及类黄酮AChE抑制剂的设计、合成及生物活性研究
|
摘要
阿尔茨海默氏症(AD),又称为早老性痴呆病,是一种中枢神经系统退行性疾病,以认知能力的丧失,严重的行为异常为特征,最终可以导致死亡。目前已经成为继心脏病、癌症、中风之后的老年人第四大杀手,严重危害着人类健康。临床上使用的治疗AD的药物以乙酰胆碱酯酶抑制剂为主,近年来研究发现,乙酰胆碱酯酶抑制剂不仅具有抑制乙酰胆碱酯酶水解的作用,而且还可以通过酶外周位点抑制淀粉样肽的聚集,起到保护神经细胞的作用。因此近年来,新型AChE抑制剂的研究一直是治疗AD的药物的热点。
本课题的工作主要分为两大部分:一是对本课题组曾得到的一个茚酮类AChE抑制剂5,6-二甲氧基-2-(4-吡咯烷-1-基甲基-苯氧基)-1-茚酮进行了多方面的结构改造:根据分子对接研究结果,通过延长中部苯环与叔胺基团之间连接链,或者用=CH_2-NH代替茚酮与苯环之间的氧从而增加分子的长度;在苯环与叔胺基团之间的连接链上引入羰基以增加与酶的氨基酸残基的相互作用;用苯乙酮和他克林代替茚酮部分等,以得到能同时和酶的外周位点和中心催化位点结合的双重抑制剂。根据上述设计思想,设计了原料易得、操作简便、收率较高的合成路线,共合成了35个茚酮类衍生物,7个苯乙酮类衍生物和8个他克林类衍生物,所有目标化合物的结构经~1H NMR、IR、ESI-MS确证。
对目标化合物进行了体外抑制胆碱酯酶试验,大部分化合物对鼠AChE和人AChE均有较强的抑制活性,而对BuChE抑制活性较弱,提示它们有较强的选择性,其中4个化合物抑制鼠AChE的IC_(50)在0.78-10 nmol/L之间,活性最好的化合物的IC_(50)达0.78nmol/L。发现该类化合物的构效关系如下:苯环与叔胺之间连接链的长度对化合物的活性有显著影响,连接链为1-4个亚甲基的化合物中,含CH_2CH_2结构单元的化合物活性最高;连接链含羰基的化合物中,具有COCH_2CH_2结构单元的化合物活性最高;与烷烃类连接链比较,插入羰基对活性具有重要作用;连接链位于苯环对位的化合物活性高于连接链位于苯环间位的化合物;苯胺亚甲基类化合物普遍具有较强的AChE抑制活性。为了更好的了解该类化合物与AChE的作用模式,对代表化合物进行了分子对接研究,结果表明该化合物可分别与AChE的外周位点,中心催化位点以及芳香峡谷中部的多个氨基酸残基发生作用。用MTT法测试了代表化合物2-67对抗H_2O_2导致的细胞存活率下降的影响,结果表明,该化合物在浓度为0.01,0.1,0.5μM时,均表现出明显的神经细胞保护作用。
本课题的第二部分根据多奈哌齐分子中的苄基哌啶部分结合于AChE的中心催化位点,而茚酮部分结合于AChE的外周位点这一特征,利用药效团迁移、杂合原理,用类黄酮骨架替代茚酮,并将类黄酮的骨架结构与苄基哌啶部分相结合,设计了一系列类黄酮.苄基哌啶杂合体。通过文献调研,选择了相应的合成路线,分别合成了黄烷酮,黄酮,异黄酮和查耳酮类衍生物共21个,所有目标化合物的结构经~1H NMR、IR、ESI-MS确证。对该系列化合物进行了AChE抑制活性测试,结果表明,大部分化合物具有中等强度的AChE抑制活性,其中异黄酮类化合物活性最好,连接链为氧原子的化合物活性高于连接链为亚甲氧基的化合物;苄基哌啶位于类黄酮B环对位的化合物活性高于位于间位的化合物。该系列中活性最好的化合物IC_(50)为93nmol/L。对它的分子对接研究表明,该化合物中苄基哌啶部分作用于酶的中心位点,而异黄酮片断则与酶的外周位点结合,与设计思想基本符合。
Alzheimer's disease(AD) is a progressive neurodegenerative disorder characterized by loss of memory and cognition.To date,the enhancement of the central cholinergic function is the mainly effective approach,mainly by means of reversible acetylcholinesterase(AChE) inhibitors.Recent studies suggested that dual-binding inhibitors not only inhibited the hydrolysis of AChE toward ACh,but also prevented the aggregation of toxicβ-amyloid(Aβ).Moreover,some AChE inhibitors possess neuroprotective activity in vivo and in vitro.In recent years,there has been a growing interest in the search for potent AChE inhibitors.
In continuring our research for dual-binding AChE inhibitors,some modifications were made on the the basis of 5,6-dimethoxy-2-(4-(pyrrolidin-1-ylmethyl) phenoxy)-2,3-dihydro-1H-inden-1-one.The length of the linker between the benzene ring and the tertiary amine was increased up to 2-4 methylene units;A carbonyl group was introduced within the linker chain;The oxygen atom between the indanone and benzene ring was replaced by =CH_2-NH;Indanone fragment was replaced by tacrine and acetophenone.35 indanone derivatives,8 tacrine derivatives and 7 acetophenone derivatives were synthesized and their structures were confirmed.The target compounds were assayed for rat AChE,human AChE and rat BuChE inhibition.Most of the compounds demonstrated potent AChE inhibitory activity and selectivity, among them,4 compounds demonstrated AChE activity with an IC_(50) within 0-10nmol/L.
To explore the possible binding conformation,a molecular modelling study of the optimum compound 2-67 was performed,and the result showed that the compound interacted well with both the catalytic and the peripheral binding sites.The neuroprotective effect of the representative compound 2-67 against H_2O_2-induced cell death was evaluated,and the result showed that the compound possessed obvious neuroprotective effect at various concentrations.
Considering that benzyl piperidine moiety can interact with AChE at the catalytic site, and the aromatic ring of flavanoid may have the chance to interact with the PAS of AChE,various flavonoids(flavone,isoflavone,flavonone or chalcone) and N-benzyl piperidine were chosen as the two pharmacophoric moieties and linked with oxygen or alkoxyl group.Thus,21 flavanoid derivatives were designed,synthesized and evaluated for their AChE inhibition activity.Most of the target compounds demonstrated moderate AChE inhibitory activity.Among them,isoflavone derivatives were more potent than other series,and the most potent compound possessed an IC_(50) of 0.093 nmol/L.
本课题的工作主要分为两大部分:一是对本课题组曾得到的一个茚酮类AChE抑制剂5,6-二甲氧基-2-(4-吡咯烷-1-基甲基-苯氧基)-1-茚酮进行了多方面的结构改造:根据分子对接研究结果,通过延长中部苯环与叔胺基团之间连接链,或者用=CH_2-NH代替茚酮与苯环之间的氧从而增加分子的长度;在苯环与叔胺基团之间的连接链上引入羰基以增加与酶的氨基酸残基的相互作用;用苯乙酮和他克林代替茚酮部分等,以得到能同时和酶的外周位点和中心催化位点结合的双重抑制剂。根据上述设计思想,设计了原料易得、操作简便、收率较高的合成路线,共合成了35个茚酮类衍生物,7个苯乙酮类衍生物和8个他克林类衍生物,所有目标化合物的结构经~1H NMR、IR、ESI-MS确证。
对目标化合物进行了体外抑制胆碱酯酶试验,大部分化合物对鼠AChE和人AChE均有较强的抑制活性,而对BuChE抑制活性较弱,提示它们有较强的选择性,其中4个化合物抑制鼠AChE的IC_(50)在0.78-10 nmol/L之间,活性最好的化合物的IC_(50)达0.78nmol/L。发现该类化合物的构效关系如下:苯环与叔胺之间连接链的长度对化合物的活性有显著影响,连接链为1-4个亚甲基的化合物中,含CH_2CH_2结构单元的化合物活性最高;连接链含羰基的化合物中,具有COCH_2CH_2结构单元的化合物活性最高;与烷烃类连接链比较,插入羰基对活性具有重要作用;连接链位于苯环对位的化合物活性高于连接链位于苯环间位的化合物;苯胺亚甲基类化合物普遍具有较强的AChE抑制活性。为了更好的了解该类化合物与AChE的作用模式,对代表化合物进行了分子对接研究,结果表明该化合物可分别与AChE的外周位点,中心催化位点以及芳香峡谷中部的多个氨基酸残基发生作用。用MTT法测试了代表化合物2-67对抗H_2O_2导致的细胞存活率下降的影响,结果表明,该化合物在浓度为0.01,0.1,0.5μM时,均表现出明显的神经细胞保护作用。
本课题的第二部分根据多奈哌齐分子中的苄基哌啶部分结合于AChE的中心催化位点,而茚酮部分结合于AChE的外周位点这一特征,利用药效团迁移、杂合原理,用类黄酮骨架替代茚酮,并将类黄酮的骨架结构与苄基哌啶部分相结合,设计了一系列类黄酮.苄基哌啶杂合体。通过文献调研,选择了相应的合成路线,分别合成了黄烷酮,黄酮,异黄酮和查耳酮类衍生物共21个,所有目标化合物的结构经~1H NMR、IR、ESI-MS确证。对该系列化合物进行了AChE抑制活性测试,结果表明,大部分化合物具有中等强度的AChE抑制活性,其中异黄酮类化合物活性最好,连接链为氧原子的化合物活性高于连接链为亚甲氧基的化合物;苄基哌啶位于类黄酮B环对位的化合物活性高于位于间位的化合物。该系列中活性最好的化合物IC_(50)为93nmol/L。对它的分子对接研究表明,该化合物中苄基哌啶部分作用于酶的中心位点,而异黄酮片断则与酶的外周位点结合,与设计思想基本符合。
Alzheimer's disease(AD) is a progressive neurodegenerative disorder characterized by loss of memory and cognition.To date,the enhancement of the central cholinergic function is the mainly effective approach,mainly by means of reversible acetylcholinesterase(AChE) inhibitors.Recent studies suggested that dual-binding inhibitors not only inhibited the hydrolysis of AChE toward ACh,but also prevented the aggregation of toxicβ-amyloid(Aβ).Moreover,some AChE inhibitors possess neuroprotective activity in vivo and in vitro.In recent years,there has been a growing interest in the search for potent AChE inhibitors.
In continuring our research for dual-binding AChE inhibitors,some modifications were made on the the basis of 5,6-dimethoxy-2-(4-(pyrrolidin-1-ylmethyl) phenoxy)-2,3-dihydro-1H-inden-1-one.The length of the linker between the benzene ring and the tertiary amine was increased up to 2-4 methylene units;A carbonyl group was introduced within the linker chain;The oxygen atom between the indanone and benzene ring was replaced by =CH_2-NH;Indanone fragment was replaced by tacrine and acetophenone.35 indanone derivatives,8 tacrine derivatives and 7 acetophenone derivatives were synthesized and their structures were confirmed.The target compounds were assayed for rat AChE,human AChE and rat BuChE inhibition.Most of the compounds demonstrated potent AChE inhibitory activity and selectivity, among them,4 compounds demonstrated AChE activity with an IC_(50) within 0-10nmol/L.
To explore the possible binding conformation,a molecular modelling study of the optimum compound 2-67 was performed,and the result showed that the compound interacted well with both the catalytic and the peripheral binding sites.The neuroprotective effect of the representative compound 2-67 against H_2O_2-induced cell death was evaluated,and the result showed that the compound possessed obvious neuroprotective effect at various concentrations.
Considering that benzyl piperidine moiety can interact with AChE at the catalytic site, and the aromatic ring of flavanoid may have the chance to interact with the PAS of AChE,various flavonoids(flavone,isoflavone,flavonone or chalcone) and N-benzyl piperidine were chosen as the two pharmacophoric moieties and linked with oxygen or alkoxyl group.Thus,21 flavanoid derivatives were designed,synthesized and evaluated for their AChE inhibition activity.Most of the target compounds demonstrated moderate AChE inhibitory activity.Among them,isoflavone derivatives were more potent than other series,and the most potent compound possessed an IC_(50) of 0.093 nmol/L.
引文
1. Sussman, J. L.; Harel, M.F., Felix; Oefner, C; Goldman, A.; Toker, L.; Silman, I.,Atomic structure of acetylcholinesterase from torpedo California:a prototypic acetylcholine-binding protein. Science (Washington, DC, United States) 1991, 253,(5022), 872-879.
2. Johnson, G.; Moore, S. W., The Peripheral Anionic Site of Acetylcholinesterase:Structure, Functions and Potential Role in Rational Drug Design. Current Pharmaceutical Design 2006,12, (2), 217-225.
3. Johnson, C. N.; Roland, A.; Upton, N., New symptomatic strategies in Alzheimer's disease. Drug Discovery Today: Therapeutic Strategies 2004, 1, (1),13-20.
4. Bartolini, M.; Bertucci, C.; Cavrini, V.; Andrisano, V., .beta.-Amyloid aggregation induced by human acetylcholinesterase: inhibition studies. Biochemical Pharmacology 2003, 65, (3), 407-416.
5. Cottingham, M. G.; Hollinshead, M. S.; Vaux, D. J. T., Amyloid Fibril Formation by a Synthetic Peptide from a Region of Human Acetylcholinesterase that Is Homologous to the Alzheimer's Amyloid-.beta. Peptide. Biochemistry 2002, 41, (46),13539-13547.
6. Nicolet, Y.; Lockridge, O.; Masson, P.; Fontecilla-Camps, J. C; Nachon, F.,Crystal structure of human butyrylcholinesterase and of its complexes with substrate and products. Journal of Biological Chemistry 2003, 278, (42), 41141-41147.
7. Rodriguez-Franco, M. I.; Fernandez-Bachiller, M. 1.; Perez, C.;Hernandez-Ledesma, B.; Bartolome, B., Novel Tacrine-Melatonin Hybrids as Dual-Acting Drugs for Alzheimer Disease, with Improved Acetylcholinesterase Inhibitory and Antioxidant Properties. Journal of Medicinal Chemistry 2006, 49, (2),459-462.
8. Pang, Y.-P.; Quiram, P.; Jelacic, T.; Hong, F.; Brimijoin, S., Highly potent,selective, and low cost bis-tetrahydroaminacrine inhibitors of acetylcholinesterase. Steps toward novel drugs for treating Alzheimer's disease. Journal of Biological Chemistry 1996,271, (39), 23646-23649.
9. Carlier, P. R.; Han, Y. F.; Chow, E. S.; Li, C. P.; Wang, H.; Lieu, T. X.; Wong, H.S.; Pang, Y. P., Evaluation of short-tether bis-THA AChE inhibitors. A further test of the dual binding site hypothesis. Bioorganic & medicinal chemistry 1999, 7, (2),351-7.
10. Rydberg, E. H.; Brumshtein, B.; Greenblatt, H. M.; Wong, D. M.; Shaya, D.;Williams, L. D.; Carlier, P. R.; Pang, Y.-P.; Silman, I.; Sussman, J. L., Complexes of Alkylene-Linked Tacrine Dimers with Torpedo californica Acetylcholinesterase:Binding of Bis(5)-tacrine Produces a Dramatic Rearrangement in the Active-Site Gorge. Journal of Medicinal Chemistry 2006,49, (18), 5491-5500.
11. Savini, L.; Campiani, G.; Gaeta, A.; Pellerano, C; Fattorusso, C.; Chiasserini, L.;Fedorko, J. M.; Saxena, A., Novel and potent tacrine-related hetero- and homobivalent ligands for acetylcholinesterase and butyrylcholinesterase. Bioorganic & Medicinal Chemistry Letters 2001,11,(13), 1779-1782.
12. Hu, M.; Lu, C. F., A facile synthesis of bis-tacrine isosteres. Tetrahedron Letters 2000,41,(11), 1815-1818.
13. Wu, L. J.; Hsiao, G.; Yen, M.-H.; Hu, M. K., Homodimeric Tacrine Congeners as Acetylcholinesterase Inhibitors. Journal of Medicinal Chemistry 2002, 45, (11),2277-2282.
14. Inestrosa, N. C; Alvarez, A.; Perez, C. A.; Moreno, R. D.; Vicente, M.; Linker, C.;Casanueva, O. I.; Soto, C; Garrido, J., Acetylcholinesterase accelerates assembly of amyloid-.beta.-peptides into Alzheimer's fibrils: possible role of the peripheral site of the enzyme. Neuron 1996, 16, (4), 881-891.
15. Bolognesi, M. L.; Andrisano, V.; Bartolini, M.; Banzi, R.; Melchiorre, C.,Propidium-Based Polyamine Ligands as Potent Inhibitors of Acetylcholinesterase and Acetylcholinesterase-Induced Amyloid-b Aggregation. Journal of Medicinal Chemistry 2005, 48, (1), 24-27.
16. Lewis, W. G.; Green, L. G.; Grynszpan, F.; Radic, Z.; Carlier, P. R.; Taylor, P.;Finn, M. G.; Sharpless, K. B., Click chemistry in situ: Acetylcholinesterase as a reaction vessel for the selective assembly of a femtomolar inhibitor from an array of building blocks. Angewandte Chemie, International Edition 2002,41, (6), 1053-1057.
17. Manetsch, R.; Krasinski, A.; Radic, Z.; Raushel, J.; Taylor, P.; Sharpless, K. B.;Kolb, H. C, In Situ Click Chemistry: Enzyme Inhibitors Made to Their Own Specifications. Journal of the American Chemical Society 2004, 126, (40),12809-12818.
18. Krasinski, A.; Radic, Z.; Manetsch, R.; Raushel, J.; Taylor, P.; Sharpless, K. B.;Kolb, H. C, In Situ Selection of Lead Compounds by Click Chemistry: Target-Guided Optimization of Acetylcholinesterase Inhibitors. Journal of the American Chemical Society 2005,127, (18), 6686-6692.
19. Dorronsoro, I.; Alonso, D.; Castro, A.; Del Monte, M.; Garcia-Palomero, E.;Martinez, A., Synthesis and biological evaluation of tacrine-thiadiazolidinone hybrids as dual acetylcholinesterase inhibitors. Archiv der Pharmazie (Weinheim, Germany) 2005,338,(1),18-23.
20. Munoz-Ruiz, P.; Rubio, L.; Garcia-Palomero, E.; Dorronsoro, I.; Monte-Millan,M. d.; Valenzuela, R.; Usan, P.; de Austria, C.; Bartolini, M.; Andrisano, V.;Bidon-Chanal, A.; Orozco, M.; Luque, F. J.; Medina, M.; Martinez, A., Design.Synthesis, and Biological Evaluation of Dual Binding Site Acetylcholinesterase Inhibitors: New Disease-Modifying Agents for Alzheimer's Disease. Journal of Medicinal Chemistry 2005, 48, (23), 7223-7233.
21. Alonso, D.; Dorronsoro, I.; Rubio, L.; Munoz, P.; Garcia-Palomero, E.; Del Monte, M.; Bidon-Chanal, A.; Orozco, M.; Luque, F. J.; Castro, A.; Medina, M.,Donepezil-tacrine hybrid related derivatives as new dual binding site inhibitors of AChE. Bioorganic & Medicinal Chemistry 2005, 13, (24), 6588-6597.
22. Elsinghorst, P. W.; Gonzalez Tanarro, C. M.; Gutschow, M., Novel Heterobivalent Tacrine Derivatives as Cholinesterase Inhibitors with Notable Selectivity Toward Butyrylcholinesterase Journal of Medicinal Chemistry 2006, 49, (25), 7540-7544.
23. Kryger, G; Silman, I.; Sussman, J. L., Structure of acetylcholinesterase complexed with E2020: implication for the design of new anti-Alzheimer drug.Structure 1999, 7, (3), 297-307.
24.Takeuchi Y,Shibata T,Suzuki E,et al.Preparation of 1-benzyl-4-[(5,6-dimethoxy-2-fluoro-1-indanon)-2-yl]methylpiperidine as acetylcholinesterase inhibitor.WO:2002020482,2002.
25.Iimura Y,Kosasa T.Preparation of 4-substituted piperidine derivatives as acetylcholinesterase inhibiting remedies for senile dementia.WO:2001016105,2001.
26.Mucke,H.,TAK-147 Takeda.Current Opinion in lnvestigational Drugs (PharmaPress Ltd.) 2001,2,(11),1595-1599.
27.Hatip-AI-Khatib,I.;Takashi,A.;Egashira,N.;Iwasaki,K.;Fujiwara,M.,Comparison of the effect of TAK-147(zanapezil) and E-2020(donepezil) on extracellular acetylcholine level and blood flow in the ventral hippocampus of freely moving rats.Brain Research 2004,1012,(1,2),169-176.
28.Liston,D.R.;Nielsen,J.A.;Villalobos,A.;Chapin,D.;Jones,S.B.;Hubbard,S.T.;Shalaby,I.A.;Ramirez,A.;Nason,D.;White,W.F.,Pharmacology of selective acetylcholinesterase inhibitors:implications for use in Alzheimer's disease.European Journal of Pharmacology 2004,486,(1),9-17.
29.Rodriguez-Franco,M.I.;Fernandez-Bachiller,M.I.;Perez,C.;Castro,A.;Martinez,A.,Design and synthesis of N-benzylpiperidine-purine derivatives as new dual inhibitors of acetyl-and butyrylcholinesterase.Bioorganic & Medicinal Chemistry 2005,13,(24),6795-6802.
30.Shao,D.;Zou,C.;Luo,C.;Tang,X.;Li,Y.,Synthesis and evaluation of tacrine-E2020 hybrids as acetylcholinesterase inhibitors for the treatment of Alzheimer's disease.Bioorganic & Medicinal Chemistry Letters 2004,14,(18),4639-4642.
31.Sheng,R.;Lin,X.;Li,J.;Jiang,Y.;Shang,Z.;Hu,Y.,Design,synthesis,and evaluation of 2-phenoxy-indan-l-one derivatives as acetylcholinesterase inhibitors.Bioorganic & Medicinal Chemistry Letters 2005,15,(17),3834-3837.
32.Piazzi,L.;Rampa,A.;Bisi,A.;Gobbi,S.;Belluti,F.;Cavalli,A.;Bartolini,M.;Andrisano,V.;Valenti,P.;Recanatini,M.,3-(4-{[Benzyl(methyl)amino]methyl}phenyl)-6,7-dimethoxy-2H-2-chromenone (AP2238) Inhibits Both Acetylcholinesterase and Acetylcholinesterase-Induced b-Amyloid Aggregation:A Dual Function Lead for Alzheimer's Disease Therapy.Journal of Medicinal Chemistry 2003,46,(12),2279-2282.
33.Piazzi,L.;Cavalli,A.;Belluti,F.;Bisi,A.;Gobbi,S.;Rizzo,S.;Bartolini,M.;Andrisano,V.;Recanatini,M.;Rampa,A.,Extensive SAR and Computational Studies of 3-{4-[(Benzylmethylamino)methyl]phenyl}-6,7-dimethoxy-2H-2-chromenone (AP2238) Derivatives Journal of Medicinal Chemistry 2007,50,(17),4250-4254.
34.Rampa,A.;Piazzi,L.;Belluti,F.;Gobbi,S.;Bisi,A.;Bartolini,M.;Andrisano,V.;Cavrini,V.;Cavalli,A.;Recanatini,M.;Valenti,P.,Acetylcholinesterase Inhibitors:SAR and Kinetic Studies on w-[N-Methyi-N-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxyaryl Derivatives.Journal of Medicinal Chemistry 2001,44,(23),3810-3820.
35.Belluti,F.;Rampa,A.;Piazzi,L.;Bisi,A.;Gobbi,S.;Bartolini,M.;Andrisano,V.;Cavalli,A.;Recanatini,M.;Valenti,P.,Cholinesterase Inhibitors:Xanthostigrnine Derivatives Blocking the Acetylcholinesterase-Induced β-Amyloid Aggregation.Journal of Medicinal Chemistry 2005,48,(13),4444-4456.
36.Piazzi,L.;Belluti,F.;Bisi,A.;Gobbi,S.;Rizzo,S.;Bartolini,M.;Andrisano,V.;Recanatini,M.;Rampa,A.,Cholinesterase inhibitors:SAR and enzyme inhibitory activity of 3-[omega-(benzylmethylamino)alkoxy]xanthen-9-ones.Bioorganic &Medicinal Chemistry 2007,15,(1),575-585.
37.Giunta,B.;Ehrhart,J.;Townsend,K.;Sun,N.;Vendrame,M.;Shytle,D.;Tan,J.;Fernandez,F.,Galantamine and nicotine have a synergistic effect on inhibition of microglial activation induced by HIV-1 gpl20.Brain Research Bulletin 2004,64,(2),165-170.
38.Maelicke,A.;Albuquerque,E.X.,Allosteric modulation of nicotinic acetylcholine receptors as a treatment strategy for Alzheimer's disease.European Journal of Pharmacology 2000,393,(1-3),165-170.
39.Ezoulin,M.J.M.;Ombetta,J.-E.;Dutertre-Catella,H.;Warnet,J.-M.;Massicot,F..Antioxidative properties of galantamine on neuronal damage induced by hydrogen peroxide in SK-N-SH cells.NeuroToxicology 2008,29,(2),270-277.
40.Guillou,C.;Mary,A.;Renko,D.Z.;Gras,E.;Thai,C.,Potent acetylcholinesterase inhibitors: design, synthesis and structure-activity relationships of alkylene linked bis-galanthamine and galanthamine-galanthaminium salts.Bioorganic & Medicinal Chemistry Letters 2000,10, (7), 637-639.
41. Mary, A.; Renko, D. Z.; Guillou, C; Thai, C., Potent Acetylcholinesterase Inhibitors: Design, Synthesis, and Structure±Activity Relationships of Bis-interacting Ligands in the Galanthamine series. Bioorganic & Medicinal Chemistry 1998, 6,(10), 1835-1850.
42. Raves, M. L.; Harel, M.; Pang, Y.-P.; Silman, I.; Kozikowski, A. P.; Sussman, J.L., Structure of acetylcholinesterase complexed with the nootropic alkaloid,(-)-huperzine A. Nature Structural Biology 1997,4, (1), 57-63.
43. Xiao Qiu Xiao, H. Y. Z., Xi Can Tang, Huperzine A attenuates amyloid -peptide fragment 25-35-induced apoptosis in rat cortical neurons via inhibiting reactive oxygen species formation and caspase-3 activation. Journal of Neuroscience Research 2002,67,(1), 30-36.
44. Zhang, H. Y.; Tang, X. C., Huperzine A attenuates the neurotoxic effect of staurosporine in primary rat cortical neurons. Neuroscience Letters 2003, 340, (2),91-94.
45. Zhang, H. Y.; Yan, H.; Tang, X. C, Huperzine A enhances the level of secretory amyloid precursor protein and protein kinase C-α in intracerebroventricular β-amyloid-(1-40) infused rats and human embryonic kidney 293 Swedish mutant cells. Neuroscience Letters 2004, 360, (1), 21-24.
46. Yan, X.; Lu, W.; Lou, W.; Tang, X., Effects of huperzine A and B on skeletal muscle and electroencephalogram. Zhongguo Yaoli Xuebao 1987, 8, (2), 117-23.
47. Camps, P.; El Achab, R.; Goerbig, D. M.; Morral, J.; Munoz-Torrero, D.; Badia,A.; Banos, J. E.; Vivas, N. M.; Barril, X.; Orozco, M.; Luque, F. J., Synthesis, in Vitro Pharmacology, and Molecular Modeling of Very Potent Tacrine-Huperzine A Hybrids as Acetylcholinesterase Inhibitors of Potential Interest for the Treatment of Alzheimer's Disease. Journal of Medicinal Chemistry 1999,42, (17), 3227-3242.
48. Camps, P.; El Achab, R.; Morral, J.; Munoz-Torrero, D.; Badia, A.; Banos, J. E.;Vivas, N. M.; Barril, X.; Orozco, M.; Luque, F. J., New tacrine-huperzine A hybrids (huprines): highly potent tight-binding acetylcholinesterase inhibitors of interest for the treatment of Alzheimer's disease. Journal of Medicinal Chemistry 2000, 43, (24),4657-4666.
49. Camps, P.; Formosa, X.; Munoz-Torrero, D.; Petrignet, J.; Badia, A.; Clos, M. V.,Synthesis and Pharmacological Evaluation of Huprine-Tacrine Heterodimers:Subnanomolar Dual Binding Site Acetylcholinesterase Inhibitors. Journal of Medicinal Chemistry 2005, 48, (6), 1701-1704.
50. Gemma, S.; Gabellieri, E.; Huleatt, P.; Fattorusso, C; Borriello, M.; Catalanotti.B.; Butini, S.; De Angelis, M.; Novellino, E.; Nacci, V.; Belinskaya, T.; Saxena, A.;Campiani, G, Discovery of Huperzine A-Tacrine Hybrids as Potent Inhibitors of Human Cholinesterases Targeting Their Midgorge Recognition Sites Journal of Medicinal Chemistry 2006,49, (11), 3421-3425.
51. Carlier, P. R.; Du, D.-M.; Han, Y.; Liu, J.; Pang, Y.-P., Potent, easily synthesized huperzine A-tacrine hybrid acetylcholinesterase inhibitors. Bioorganic & Medicinal Chemistry Letters 1999,9, (16), 2335-2338.
52. Carlier PR, Du D, Han Y, et al. Dimerization of an inactive fragment of huperzine A produces a drug with twice the potency of natural porduct. Angew Chem Int Ed 2000,39,(10), 1775-1777.
53. Carlier PR, Han YF, Pang YP, et al. Preparation of dimeric quinolonyl amines related compounds as cholinesterase inhibitors GB: 2360518.
54. Jin GY, He XC, Zhang HY, et al. Synthesis of alkylene-linked dimers of (-)-huperzine A. Chinese Chemical Letters 2002, 13, (1), 23-26.
55. Jin Gy, Luo XM, He XC, et al. Synthesis and docking studies of alkylene-linked dimers of (-)-huperzine A. Arzneimittel-Forschung 2003, 53, (11), 753-757.
56. Feng, S.; Xia, Y.; Han, D.; Zheng, C; He, X.; Tang , X.; Bai, D., Synthesis and acetylcholinesterase inhibition of derivatives of huperzine B. Bioorganic & Medicinal Chemistry Letters 2005, 15, (3), 523-526.
57. Feng, S.; Wang, Z.; He, X.; Zheng, S.; Xia, Y.; Jiang, H.; Tang, X.; Bai, D.,Bis-huperzine B: Highly Potent and Selective Acetylcholinesterase Inhibitors. Journal of Medicinal Chemistry 2005,48, (3), 655-657.
58. He, X.-C.; Feng, S.; Wang, Z.-F.; Shi, Y.; Zheng, S.; Xia, Y.; Jiang, H.; Tang ,X.-c; Bai, D., Study on dual-site inhibitors of acetylcholinesterase: Highly potent derivatives of bis- and bifunctional huperzine B. Bioorganic & Medicinal Chemistry 2007,15,(3), 1394-1408.
59. Sauvaitre, T.; Barlier, M.; Herlem, D.; Gresh, N.; Chiaroni, A.; Guenard, D.;Guillou, C, New Potent Acetylcholinesterase Inhibitors in the Tetracyclic Triterpene Series. Journal of Medicinal Chemistry 2007, 50, (22), 5311-5323.
60. Kapkova, P.; Stiefl, N.; Suerig, U.; Engels, B.; Baumann, K.; Holzgrabe, U.,Synthesis, biological activity, and docking studies of new acetylcholinesterase inhibitors of the bispyridinium type. Archiv der Pharmazie (Weinheim, Germany) 2003, 336, (11), 523-540.
61. Alptuezuen, V.; Kapkova, P.; Baumann, K.; Erciyas, E.; Holzgrabe, U., Synthesis and biological activity of pyridinium-type acetylcholinesterase inhibitors. Journal of Pharmacy and Pharmacology 2003, 55, (10), 1397-1404.
62. Kapkova, P.; Alptuezuen, V.; Frey, P.; Erciyas, E.; Holzgrabe, U., Search for dual function inhibitors for Alzheimer's disease: Synthesis and biological activity of acetylcholinesterase inhibitors of pyridinium-type and their Aβ fibril formation inhibition capacity. Bioorganic & Medicinal Chemistry 2006,14, (2), 472-478.
63. Pietsch, M.; Guetschow, M., Synthesis of Tricyclic l,3-Oxazin-4-ones and Kinetic Analysis of Cholesterol Esterase and Acetylcholinesterase Inhibition. Journal of Medicinal Chemistry 2005,48, (26), 8270-8288.
64. Tang, H.; Ning, F.-X.; Wei, Y.-B.; Huang, S.-L.; Huang, Z.-S.; Chan, A. S.-C.; Gu,L.-Q., Derivatives of oxoisoaporphine alkaloids: A novel class of selective acetylcholinesterase inhibitors. Bioorganic & Medicinal Chemistry Letters 2007, 17,(13), 3765-3768.
65. Decker, M., Novel inhibitors of acetyl- and butyrylcholinesterase derived from the alkaloids dehydroevodiamine and rutaecarpine. European Journal of Medicinal Chemistry 2005,40, (3), 305-313.
66. Decker, M.; Krauth, F.; Lehmann, J., Novel tricyclic quinazolinimines and related tetracyclic nitrogen bridgehead compounds as cholinesterase inhibitors with selectivity towards butyrylcholinesterase. Bioorganic & Medicinal Chemistry 2006,14,(6), 1966-1977.
67. Decker, M., Homobivalent Quinazolinimines as Novel Nanomolar Inhibitors of Cholinesterases with Dirigible Selectivity toward Butyrylcholinesterase Journal of Medicinal Chemistry 2006,49, (18), 5411-5413.
68. Rosini, M.; Andrisano, V.; Bartolini, M.; Bolognesi, M. L.; Hrelia, P.; Minarini,A.; Tarozzi, A.; Melchiorre, C, Rational Approach To Discover Multipotent Anti-Alzheimer Drugs. Journal of Medicinal Chemistry 2005,48, (2), 360-363.
69. Srinivasan, V.; Pandi-Perumal, S. R.; Maestroni, G. J. M.; Esquifino, A. I.;Hardeland, R.; Cardinali, D. P., Role of melatonin in neurodegenerative diseases.Neurotoxicity Research 2005, 7, (4), 293-318.
70. Marco-Contelles, J.; Leon, R.; de Rios, C.; Guglietta, A.; Terencio, J.; Lopez, M.G; Garcia, A. G; Villarroya, M., Novel Multipotent Tacrine-Dihydropyridine Hybrids with Improved Acetylcholinesterase Inhibitory and Neuroprotective Activities as Potential Drugs for the Treatment of Alzheimer's Disease. Journal of Medicinal Chemistry 2006,49, (26), 7607-7610.
71. Elsinghorst, P. W.; Cieslik, J. S.; Mohr, K.; Trankle, C.; Gutschow, M., First Gallamine-Tacrine Hybrid: Design and Characterization at Cholinesterases and the M2 Muscarinic Receptor Journal of Medicinal Chemistry 2007, 50, (23), 5685-5695.
72. Blandina, P.; Goldfarb, J.; Green, J. P., Activation of a 5-HT3 receptor releases dopamine from rat striatal slice. European Journal of Pharmacology 1988, 155, (3),349-50.
73. Barnes, J. M.; Barnes, N. M.; Costall, B.; Naylor, R. J.; Tyers, M. B., 5-HT3 receptors mediate inhibition of acetylcholine release in cortical tissue. Nature (London, United Kingdom) 1989, 338, (6218), 762-3.
74. Cappelli, A.; Gallelli, A.; Manini, M.; Anzini, M.; Mennuni, L.; Makovec, F.;Menziani, M. C; Alcaro, S.; Ortuso, F.; Vomero, S., Further Studies on the Interaction of the 5-Hydroxytryptamine3 (5-HT3) Receptor with Arylpiperazine Ligands.Development of a New 5-HT3 Receptor Ligand Showing Potent Acetylcholinesterase Inhibitory Properties. Journal of Medicinal Chemistry 2005,48, (10), 3564-3575.
75. Piazzi, L.; Cavalli, A.; Colizzi, F.; Belluti, F.; Bartolini, M.; Mancini, F.;Recanatini, M.; Andrisano, V.; Rampa, A., Multi-target-directed coumarin derivatives:hAChE and BACE1 inhibitors as potential anti-Alzheimer compounds. Bioorganic & Medicinal Chemistry Letters 2008,18, (1), 423-426.
76. Toda, N.; Tago, K.; Marumoto, S.; Takami, K.; Ori, M.; Yamada, N.; Koyama, K.;Naruto, S.; Abe, K.; Yamazaki, R., Design, synthesis and structure-Activity relationships of dual inhibitors of acetylcholinesterase and serotonin transporter as potential agents for Alzheimer's disease. Bioorganic & Medicinal Chemistry 2003, 11,(9), 1935-1955.
77. Toda, N.; Tago, K.; Marumoto, S.; Takami, K.; Ori, M.; Yamada, N.; Koyama, K.;Naruto, S.; Abe, K., A conformational restriction approach to the development of dual inhibitors of acetylcholinesterase and serotonin transporter as potential agents for Alzheimer's disease. Bioorganic & Medicinal Chemistry 2003,11, (20), 4389-4415.
78. Sterling, J.; Herzig, Y.; Goren, T.; Finkelstein, N.; Lerner, D.; Goldenberg, W.,Novel Dual Inhibitors of AChE and MAO Derived from Hydroxy Aminoindan and Phenethylamine as Potential Treatment for Alzheimer's Disease. Journal of Medicinal Chemistry 2002,45, (24), 5260-5279.
79. Poltyrev, T.; Gorodetsky, E.; Bejar, C; Schorer-Apelbaum, D.; Weinstock. M.,Effect of chronic treatment with ladostigil (TV-3326) on anxiogenic and depressive-like behaviour and on activity of the hypothalamic-pituitary-adrenal axis in male and female prenatally stressed rats. Psychopharmacology (Berlin, Germany) 2005,181,(1), 118-125.
80. Sussman, J. L.; Harel, M.; Frolow, F.; Oefher, C; Goldman, A.; Toker, L.; Silman,I., Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein. Science (Washington, DC, United States) 1991, 253,(5022), 872-9.
81. De Ferrari, G. V.; Canales, M. A.; Shin, I.; Weiner, L. M.; Silman, I.; Inestrosa, N.C, A structural motif of acetylcholinesterase that promotes amyloid beta-peptide fibril formation. Biochemistry 2001,40, (35), 10447-10457.
82. Bartolini, M.; Bertucci, C; Cavrini, V.; Andrisano, V., beta.-Amyloid aggregation induced by human acetylcholinesterase:inhibition studies.Biochemical Pharmacology 2003,65,(3),407-416.
83.Giacobini,E.,Cholinesterases:New Roles in Brain Function and in Alzheimer's Disease.Neurochemical Research 2003,28,(3-4),515-522.
84.Pang,Y.-P.K.,A.,Prediction of the binding sites of huperzine A in acetylcholinesterase by docking studies,d.Comput-Aided Mol.Des.1994,(8),669-681.
85.Bose,N.K.;Chaudhury,D.N.,Isocoumarins.I.Preparation and cyclization of 2-carboxy-4,5-dimethoxyphenylacetaldehyde.J.lndian Chem.Soc.1965,42,(4),211-14.
86.Seed,A.J.;Sonpatki,V.;Herbert,M.R.,3-(4-bromobenzoyl)propanoic acid.Organic Syntheses 2002,79 204-208.
87.Guiso,M.;Bianco,A.;Marra,C.;Cavarischia,C.,One-pot synthesis of 6-hydroxyisochromans:The example of demethyl-oxa-coclaurine.European Journal of Organic Chemistry 2003,(17),3407-3411.
88.Ruchirawat,S.;Mutarapat,T.,An efficient synthesis of lamellarin alkaloids:synthesis of lamellarin G trimethyl ether.Tetrahedron Letters 2001,42,(6),1205-1208.
89.Tramontini,M.,Advances in the chemistry of Mannich bases.Synthesis 1973,(12),703-75.
90.陈芬儿.有机药物合成法 145 替米哌隆的合成
91.Sheng,R.;Lin,X.;Li,J.;Jiang,Y.;Shang,Z.;Hu,Y.,Design,synthesis,and evaluation of 2-phenoxy-indan-l-one derivatives as acetylcholinesterase inhibitors.Bioorganic & Medicinal Chemistry Letters 2005,15,(17),3834-3837.
92.Belluti,F.;Rampa,A.;Piazzi,L.;Bisi,A.;Gobbi,S.;Bartolini,M.;Andrisano,V.;Cavalli,A.;Recanatini,M.;Valenti,P.,Cholinesterase Inhibitors:Xanthostigrnine Derivatives Blocking the Acetylcholinesterase-Induced.beta.-Amyloid Aggregation.Journal of Medicinal Chemistry 2005,48,(13),4444-4456.
93.Recanatini,M.;Cavalli,A.;Belluti,F.;Piazzi,L.;Rampa,A.;Bisi,A.;Gobbi,S.;Valenti,P.;Andrisano,V.;Bartolini,M.;Cavrini,V.,SAR of 9-Amino-1,2,3,4-tetrahydroacridine-Based Acetylcholinesterase Inhibitors:Synthesis,Enzyme Inhibitory Activity,QSAR,and Structure-Based CoMFA of Tacrine Analogues.Journal of Medicinal Chemistry 2000,43,(10),2007-2018.
94.Wang,X.D.;Chen,X.Q.;Yang,H.H.;Hu,G.Y.,Comparison of the effects of cholinesterase inhibitors on[3H]MK-801 binding in rat cerebral cortex.Neuroscience letters 1999,272,(1),21-24.
95.Akasofu,S.;Kosasa,T.;Kimura,M.;Kubota,A.,Protective effect of Donepezil in a primary culture of rat cortical neurons exposed to oxygen-glucose deprivation.European Journal of Pharmacology 2003,472,(1-2),57-63.
96.早老性痴呆症的治疗药物盐酸多奈哌齐的开发应用,国外医药抗生素分册,2000,21(3):232-235。.
97.Sugimoto,H.O.,Hiroo;Arai,Yasuo;Iimura,Youichi;Yamanishi,Yoshiharu,Research and development of donepezil hydrochloride,a new type of acetylcholinesterase inhibitor.Japanese Journal of Pharmacology 2002,89,(1),7-20.
98.Barltrop,J.A.,Synthesis of analgesic substances.Journal of the Chemical Society,1946,958-65.
99.Koul,S.;Singh,B.;Taneja,S.C.;Qazi,G.N.,New chemo and chemo-enzymatic synthesis of β-benzyl-γ-butyrolactones.Tetrahedron 2003,59,(19),3487-3491.
100.Yi,C.S.;Martinelli,L.C.;Blanton,C.D.,Jr.,Synthesis of N-methyl-1-oxa-5-aza[10]paracyclophane:a conformationally restricted analog of phenoxypropylamines.Journal of Organic Chemistry 1978,43,(3),405-9.
101.Zheng,H.;Gao,W.;Ji,X.;Zhang,S.,Improved method for synthesis of Tyrosol.Zhongguo Yaowu Huaxue Zazhi 2002,12,(3),166-167.
102.Holshouser,M.H.;Kolb,M.,Facile synthesis of glycol metabolites of phenethylamine drugs Journal of Pharmaceutical Sciences 1986,75,(6),619-21.
103.Psiorz,M.;Heider,J.;Bombard,A.;Hauel,N.;Noll,K.;Narr,B.;Lillie,C.;Kobinger,W.;Daemmgen,J.Preparation,formulation,and testing of tetrahydronaphthalene and indan derivatives as bradycardic agents.DE 3630903,1988.
104.Srinivasa,G.R.;Abiraj,K.;Gowda,D.C.,Polymer-supported formate and zinc:a novel system for the transfer hydrogenation of aromatic nitro compounds.lndian Journal of Chemistry,Section B:Organic Chemistry Including Medicinal Chemistry 2006,45B,(1),297-301.
105.Ohta,S.;Okamoto,M.,Synthesis of carbonyl compounds via biogenetic-type transamination reaction Synthesis 1982,(9),756-8.
106.Wang,R.;Guan,Y.,Selective reductive alkylation of secondary amines with carbonyl compounds.Gaodeng Xuexiao Huaxue Xuebao 1990,11,(8),894-6.
107.Jacob,J.N.;Nichols,D.E.;Kohli,J.D.;Glock,D.,Dopamine agonist properties of N-alkyl-4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinolines.Journal of Medicinal Chemistry.1981,24,(8),1013-15.
108.Recanatini,M.;Cavalli,A.;Belluti,F.;Piazzi,L.;Rampa,A.;Bisi,A.;Gobbi,S.;Valenti,P.;Andrisano,V.;Bartolini,M.;Cavrini,V.,SAR of 9-Amino-l,2,3,4-tetrahydroacridine-Based Acetylcholinesterase Inhibitors:Synthesis,Enzyme Inhibitory Activity,QSAR,and Structure-Based CoMFA of Tacrine Analogues.Journal of Medicinal Chemistry 2000,43,(10),2007-2018.
109.Li,J.-r.;Han,F.-b.;Yang,X.-h.;Li,W.-t.;Ma,S.-I.,Syntheses and characterizations of tacrine and its derivatives.Hecheng Huaxue 2005,13,(2),160-162.
110.Gilgun-Sherki,Y.;Melamed,E.;Often,D.,Antioxidant treatment in Alzheimer's disease:Current state.Journal of Molecular Neuroscience 2003,21,(1),1-11.
111.Knowles,M.;Kingsport,T.;Rochester,N.Process for production of 2,4,5-trihydroxy-acetophenone.US:2763691.
112.Xi,F.;Liang,X.;Lu,Y.,A new synthetic method for some 2-hydroxy-4,5-dialkoxy-acetophenones.Huaxue Shiji 1990,12,(5),299-312.
113.Correa,R.;Pereira,M.A.S.;Buffon,D.;Dos Santos,L.;Cechinel Filho,V.;Santos,A.R.S.;Nunes,R.J.,Antinociceptive properties of chalcones.Structure-activity relationships.Archiv der Pharmazie 2001,334,(10),332-334..
114.Xiao,L.;Tan,W.;Li,Y.,First total synthesis of 0-kenusanone B.Synthetic Communications 1998,28,(15),2861-2869.
115.Mitsunobu,O.,The use of diethyl azodicarboxylate and triphenylphosphine in synthesis and transformation of natural products. Synthesis 1981, (1), 1-28..
116.Miko, T.; Ligneau, X.; Pertz, H. H.; Ganellin, C. R.; Arrang, J.-M.; Schwartz,J.-C; Schunack, W.; Stark, H., Novel Nonimidazole Histamine H3 Receptor Antagonists: l-(4-(Phenoxymethyl)benzyl)piperidines and Related Compounds.Journal of Medicinal Chemistry 2003,46, (8), 1523-1530.
117.Mavel, S.; Dikic, B.; Palakas, S.; Emond, P.; Greguric, I.; Gomez de Gracia, A.;Mattner, F.; Garrigos, M., Synthesis and biological evaluation of a series of flavone derivatives as potential radioligands for imaging the multidrug resistance-associated protein 1 (ABCC1/MRP1) Bioorganic & Medicinal Chemistry 2006, 14, (5),1599-1607.
118.Tsukayama, M.; Wada, H.; Kawamura, Y.; Yamashita, K.; Nishiuchi, M.,Regioselective synthesis of 6-alkyl- and 6-prenylpolyhydroxyisoflavones and 6-alkylcoumaronochromone derivatives. Chemical & Pharmaceutical Bulletin 2004,52,(11), 1285-1289.
119.Kawamura, Y.; Maruyama, M.; Tokuoka, T.; Tsukayama, M., Synthesis of isoflavones from 2'-hydroxychalcones using poly[4-(diacetoxy)iodo]styrene or related hypervalent iodine reagent. Synthesis 2002, (17), 2490-2496.
120. Doucet-Personeni, C; Bentley, P. D.; Fletcher, R. J.; Kinkaid, A.; Kryger, G.;Pirard, B.; Taylor, A., A Structure-Based Design Approach to the Development of Novel, Reversible AChE Inhibitors. Journal of Medicinal Chemistry 2001, 44, (20),3203-3215.
121. Diouf, O.; Depreux, P.; Chavatte, P.; Poupaert, J. H., Synthesis and preliminary pharmacological results on new naphthalene derivatives as 5-HT4 receptor ligands. European Journal of Medicinal Chemistry 2000, 35, (7 & 8),699-706.
2. Johnson, G.; Moore, S. W., The Peripheral Anionic Site of Acetylcholinesterase:Structure, Functions and Potential Role in Rational Drug Design. Current Pharmaceutical Design 2006,12, (2), 217-225.
3. Johnson, C. N.; Roland, A.; Upton, N., New symptomatic strategies in Alzheimer's disease. Drug Discovery Today: Therapeutic Strategies 2004, 1, (1),13-20.
4. Bartolini, M.; Bertucci, C.; Cavrini, V.; Andrisano, V., .beta.-Amyloid aggregation induced by human acetylcholinesterase: inhibition studies. Biochemical Pharmacology 2003, 65, (3), 407-416.
5. Cottingham, M. G.; Hollinshead, M. S.; Vaux, D. J. T., Amyloid Fibril Formation by a Synthetic Peptide from a Region of Human Acetylcholinesterase that Is Homologous to the Alzheimer's Amyloid-.beta. Peptide. Biochemistry 2002, 41, (46),13539-13547.
6. Nicolet, Y.; Lockridge, O.; Masson, P.; Fontecilla-Camps, J. C; Nachon, F.,Crystal structure of human butyrylcholinesterase and of its complexes with substrate and products. Journal of Biological Chemistry 2003, 278, (42), 41141-41147.
7. Rodriguez-Franco, M. I.; Fernandez-Bachiller, M. 1.; Perez, C.;Hernandez-Ledesma, B.; Bartolome, B., Novel Tacrine-Melatonin Hybrids as Dual-Acting Drugs for Alzheimer Disease, with Improved Acetylcholinesterase Inhibitory and Antioxidant Properties. Journal of Medicinal Chemistry 2006, 49, (2),459-462.
8. Pang, Y.-P.; Quiram, P.; Jelacic, T.; Hong, F.; Brimijoin, S., Highly potent,selective, and low cost bis-tetrahydroaminacrine inhibitors of acetylcholinesterase. Steps toward novel drugs for treating Alzheimer's disease. Journal of Biological Chemistry 1996,271, (39), 23646-23649.
9. Carlier, P. R.; Han, Y. F.; Chow, E. S.; Li, C. P.; Wang, H.; Lieu, T. X.; Wong, H.S.; Pang, Y. P., Evaluation of short-tether bis-THA AChE inhibitors. A further test of the dual binding site hypothesis. Bioorganic & medicinal chemistry 1999, 7, (2),351-7.
10. Rydberg, E. H.; Brumshtein, B.; Greenblatt, H. M.; Wong, D. M.; Shaya, D.;Williams, L. D.; Carlier, P. R.; Pang, Y.-P.; Silman, I.; Sussman, J. L., Complexes of Alkylene-Linked Tacrine Dimers with Torpedo californica Acetylcholinesterase:Binding of Bis(5)-tacrine Produces a Dramatic Rearrangement in the Active-Site Gorge. Journal of Medicinal Chemistry 2006,49, (18), 5491-5500.
11. Savini, L.; Campiani, G.; Gaeta, A.; Pellerano, C; Fattorusso, C.; Chiasserini, L.;Fedorko, J. M.; Saxena, A., Novel and potent tacrine-related hetero- and homobivalent ligands for acetylcholinesterase and butyrylcholinesterase. Bioorganic & Medicinal Chemistry Letters 2001,11,(13), 1779-1782.
12. Hu, M.; Lu, C. F., A facile synthesis of bis-tacrine isosteres. Tetrahedron Letters 2000,41,(11), 1815-1818.
13. Wu, L. J.; Hsiao, G.; Yen, M.-H.; Hu, M. K., Homodimeric Tacrine Congeners as Acetylcholinesterase Inhibitors. Journal of Medicinal Chemistry 2002, 45, (11),2277-2282.
14. Inestrosa, N. C; Alvarez, A.; Perez, C. A.; Moreno, R. D.; Vicente, M.; Linker, C.;Casanueva, O. I.; Soto, C; Garrido, J., Acetylcholinesterase accelerates assembly of amyloid-.beta.-peptides into Alzheimer's fibrils: possible role of the peripheral site of the enzyme. Neuron 1996, 16, (4), 881-891.
15. Bolognesi, M. L.; Andrisano, V.; Bartolini, M.; Banzi, R.; Melchiorre, C.,Propidium-Based Polyamine Ligands as Potent Inhibitors of Acetylcholinesterase and Acetylcholinesterase-Induced Amyloid-b Aggregation. Journal of Medicinal Chemistry 2005, 48, (1), 24-27.
16. Lewis, W. G.; Green, L. G.; Grynszpan, F.; Radic, Z.; Carlier, P. R.; Taylor, P.;Finn, M. G.; Sharpless, K. B., Click chemistry in situ: Acetylcholinesterase as a reaction vessel for the selective assembly of a femtomolar inhibitor from an array of building blocks. Angewandte Chemie, International Edition 2002,41, (6), 1053-1057.
17. Manetsch, R.; Krasinski, A.; Radic, Z.; Raushel, J.; Taylor, P.; Sharpless, K. B.;Kolb, H. C, In Situ Click Chemistry: Enzyme Inhibitors Made to Their Own Specifications. Journal of the American Chemical Society 2004, 126, (40),12809-12818.
18. Krasinski, A.; Radic, Z.; Manetsch, R.; Raushel, J.; Taylor, P.; Sharpless, K. B.;Kolb, H. C, In Situ Selection of Lead Compounds by Click Chemistry: Target-Guided Optimization of Acetylcholinesterase Inhibitors. Journal of the American Chemical Society 2005,127, (18), 6686-6692.
19. Dorronsoro, I.; Alonso, D.; Castro, A.; Del Monte, M.; Garcia-Palomero, E.;Martinez, A., Synthesis and biological evaluation of tacrine-thiadiazolidinone hybrids as dual acetylcholinesterase inhibitors. Archiv der Pharmazie (Weinheim, Germany) 2005,338,(1),18-23.
20. Munoz-Ruiz, P.; Rubio, L.; Garcia-Palomero, E.; Dorronsoro, I.; Monte-Millan,M. d.; Valenzuela, R.; Usan, P.; de Austria, C.; Bartolini, M.; Andrisano, V.;Bidon-Chanal, A.; Orozco, M.; Luque, F. J.; Medina, M.; Martinez, A., Design.Synthesis, and Biological Evaluation of Dual Binding Site Acetylcholinesterase Inhibitors: New Disease-Modifying Agents for Alzheimer's Disease. Journal of Medicinal Chemistry 2005, 48, (23), 7223-7233.
21. Alonso, D.; Dorronsoro, I.; Rubio, L.; Munoz, P.; Garcia-Palomero, E.; Del Monte, M.; Bidon-Chanal, A.; Orozco, M.; Luque, F. J.; Castro, A.; Medina, M.,Donepezil-tacrine hybrid related derivatives as new dual binding site inhibitors of AChE. Bioorganic & Medicinal Chemistry 2005, 13, (24), 6588-6597.
22. Elsinghorst, P. W.; Gonzalez Tanarro, C. M.; Gutschow, M., Novel Heterobivalent Tacrine Derivatives as Cholinesterase Inhibitors with Notable Selectivity Toward Butyrylcholinesterase Journal of Medicinal Chemistry 2006, 49, (25), 7540-7544.
23. Kryger, G; Silman, I.; Sussman, J. L., Structure of acetylcholinesterase complexed with E2020: implication for the design of new anti-Alzheimer drug.Structure 1999, 7, (3), 297-307.
24.Takeuchi Y,Shibata T,Suzuki E,et al.Preparation of 1-benzyl-4-[(5,6-dimethoxy-2-fluoro-1-indanon)-2-yl]methylpiperidine as acetylcholinesterase inhibitor.WO:2002020482,2002.
25.Iimura Y,Kosasa T.Preparation of 4-substituted piperidine derivatives as acetylcholinesterase inhibiting remedies for senile dementia.WO:2001016105,2001.
26.Mucke,H.,TAK-147 Takeda.Current Opinion in lnvestigational Drugs (PharmaPress Ltd.) 2001,2,(11),1595-1599.
27.Hatip-AI-Khatib,I.;Takashi,A.;Egashira,N.;Iwasaki,K.;Fujiwara,M.,Comparison of the effect of TAK-147(zanapezil) and E-2020(donepezil) on extracellular acetylcholine level and blood flow in the ventral hippocampus of freely moving rats.Brain Research 2004,1012,(1,2),169-176.
28.Liston,D.R.;Nielsen,J.A.;Villalobos,A.;Chapin,D.;Jones,S.B.;Hubbard,S.T.;Shalaby,I.A.;Ramirez,A.;Nason,D.;White,W.F.,Pharmacology of selective acetylcholinesterase inhibitors:implications for use in Alzheimer's disease.European Journal of Pharmacology 2004,486,(1),9-17.
29.Rodriguez-Franco,M.I.;Fernandez-Bachiller,M.I.;Perez,C.;Castro,A.;Martinez,A.,Design and synthesis of N-benzylpiperidine-purine derivatives as new dual inhibitors of acetyl-and butyrylcholinesterase.Bioorganic & Medicinal Chemistry 2005,13,(24),6795-6802.
30.Shao,D.;Zou,C.;Luo,C.;Tang,X.;Li,Y.,Synthesis and evaluation of tacrine-E2020 hybrids as acetylcholinesterase inhibitors for the treatment of Alzheimer's disease.Bioorganic & Medicinal Chemistry Letters 2004,14,(18),4639-4642.
31.Sheng,R.;Lin,X.;Li,J.;Jiang,Y.;Shang,Z.;Hu,Y.,Design,synthesis,and evaluation of 2-phenoxy-indan-l-one derivatives as acetylcholinesterase inhibitors.Bioorganic & Medicinal Chemistry Letters 2005,15,(17),3834-3837.
32.Piazzi,L.;Rampa,A.;Bisi,A.;Gobbi,S.;Belluti,F.;Cavalli,A.;Bartolini,M.;Andrisano,V.;Valenti,P.;Recanatini,M.,3-(4-{[Benzyl(methyl)amino]methyl}phenyl)-6,7-dimethoxy-2H-2-chromenone (AP2238) Inhibits Both Acetylcholinesterase and Acetylcholinesterase-Induced b-Amyloid Aggregation:A Dual Function Lead for Alzheimer's Disease Therapy.Journal of Medicinal Chemistry 2003,46,(12),2279-2282.
33.Piazzi,L.;Cavalli,A.;Belluti,F.;Bisi,A.;Gobbi,S.;Rizzo,S.;Bartolini,M.;Andrisano,V.;Recanatini,M.;Rampa,A.,Extensive SAR and Computational Studies of 3-{4-[(Benzylmethylamino)methyl]phenyl}-6,7-dimethoxy-2H-2-chromenone (AP2238) Derivatives Journal of Medicinal Chemistry 2007,50,(17),4250-4254.
34.Rampa,A.;Piazzi,L.;Belluti,F.;Gobbi,S.;Bisi,A.;Bartolini,M.;Andrisano,V.;Cavrini,V.;Cavalli,A.;Recanatini,M.;Valenti,P.,Acetylcholinesterase Inhibitors:SAR and Kinetic Studies on w-[N-Methyi-N-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxyaryl Derivatives.Journal of Medicinal Chemistry 2001,44,(23),3810-3820.
35.Belluti,F.;Rampa,A.;Piazzi,L.;Bisi,A.;Gobbi,S.;Bartolini,M.;Andrisano,V.;Cavalli,A.;Recanatini,M.;Valenti,P.,Cholinesterase Inhibitors:Xanthostigrnine Derivatives Blocking the Acetylcholinesterase-Induced β-Amyloid Aggregation.Journal of Medicinal Chemistry 2005,48,(13),4444-4456.
36.Piazzi,L.;Belluti,F.;Bisi,A.;Gobbi,S.;Rizzo,S.;Bartolini,M.;Andrisano,V.;Recanatini,M.;Rampa,A.,Cholinesterase inhibitors:SAR and enzyme inhibitory activity of 3-[omega-(benzylmethylamino)alkoxy]xanthen-9-ones.Bioorganic &Medicinal Chemistry 2007,15,(1),575-585.
37.Giunta,B.;Ehrhart,J.;Townsend,K.;Sun,N.;Vendrame,M.;Shytle,D.;Tan,J.;Fernandez,F.,Galantamine and nicotine have a synergistic effect on inhibition of microglial activation induced by HIV-1 gpl20.Brain Research Bulletin 2004,64,(2),165-170.
38.Maelicke,A.;Albuquerque,E.X.,Allosteric modulation of nicotinic acetylcholine receptors as a treatment strategy for Alzheimer's disease.European Journal of Pharmacology 2000,393,(1-3),165-170.
39.Ezoulin,M.J.M.;Ombetta,J.-E.;Dutertre-Catella,H.;Warnet,J.-M.;Massicot,F..Antioxidative properties of galantamine on neuronal damage induced by hydrogen peroxide in SK-N-SH cells.NeuroToxicology 2008,29,(2),270-277.
40.Guillou,C.;Mary,A.;Renko,D.Z.;Gras,E.;Thai,C.,Potent acetylcholinesterase inhibitors: design, synthesis and structure-activity relationships of alkylene linked bis-galanthamine and galanthamine-galanthaminium salts.Bioorganic & Medicinal Chemistry Letters 2000,10, (7), 637-639.
41. Mary, A.; Renko, D. Z.; Guillou, C; Thai, C., Potent Acetylcholinesterase Inhibitors: Design, Synthesis, and Structure±Activity Relationships of Bis-interacting Ligands in the Galanthamine series. Bioorganic & Medicinal Chemistry 1998, 6,(10), 1835-1850.
42. Raves, M. L.; Harel, M.; Pang, Y.-P.; Silman, I.; Kozikowski, A. P.; Sussman, J.L., Structure of acetylcholinesterase complexed with the nootropic alkaloid,(-)-huperzine A. Nature Structural Biology 1997,4, (1), 57-63.
43. Xiao Qiu Xiao, H. Y. Z., Xi Can Tang, Huperzine A attenuates amyloid -peptide fragment 25-35-induced apoptosis in rat cortical neurons via inhibiting reactive oxygen species formation and caspase-3 activation. Journal of Neuroscience Research 2002,67,(1), 30-36.
44. Zhang, H. Y.; Tang, X. C., Huperzine A attenuates the neurotoxic effect of staurosporine in primary rat cortical neurons. Neuroscience Letters 2003, 340, (2),91-94.
45. Zhang, H. Y.; Yan, H.; Tang, X. C, Huperzine A enhances the level of secretory amyloid precursor protein and protein kinase C-α in intracerebroventricular β-amyloid-(1-40) infused rats and human embryonic kidney 293 Swedish mutant cells. Neuroscience Letters 2004, 360, (1), 21-24.
46. Yan, X.; Lu, W.; Lou, W.; Tang, X., Effects of huperzine A and B on skeletal muscle and electroencephalogram. Zhongguo Yaoli Xuebao 1987, 8, (2), 117-23.
47. Camps, P.; El Achab, R.; Goerbig, D. M.; Morral, J.; Munoz-Torrero, D.; Badia,A.; Banos, J. E.; Vivas, N. M.; Barril, X.; Orozco, M.; Luque, F. J., Synthesis, in Vitro Pharmacology, and Molecular Modeling of Very Potent Tacrine-Huperzine A Hybrids as Acetylcholinesterase Inhibitors of Potential Interest for the Treatment of Alzheimer's Disease. Journal of Medicinal Chemistry 1999,42, (17), 3227-3242.
48. Camps, P.; El Achab, R.; Morral, J.; Munoz-Torrero, D.; Badia, A.; Banos, J. E.;Vivas, N. M.; Barril, X.; Orozco, M.; Luque, F. J., New tacrine-huperzine A hybrids (huprines): highly potent tight-binding acetylcholinesterase inhibitors of interest for the treatment of Alzheimer's disease. Journal of Medicinal Chemistry 2000, 43, (24),4657-4666.
49. Camps, P.; Formosa, X.; Munoz-Torrero, D.; Petrignet, J.; Badia, A.; Clos, M. V.,Synthesis and Pharmacological Evaluation of Huprine-Tacrine Heterodimers:Subnanomolar Dual Binding Site Acetylcholinesterase Inhibitors. Journal of Medicinal Chemistry 2005, 48, (6), 1701-1704.
50. Gemma, S.; Gabellieri, E.; Huleatt, P.; Fattorusso, C; Borriello, M.; Catalanotti.B.; Butini, S.; De Angelis, M.; Novellino, E.; Nacci, V.; Belinskaya, T.; Saxena, A.;Campiani, G, Discovery of Huperzine A-Tacrine Hybrids as Potent Inhibitors of Human Cholinesterases Targeting Their Midgorge Recognition Sites Journal of Medicinal Chemistry 2006,49, (11), 3421-3425.
51. Carlier, P. R.; Du, D.-M.; Han, Y.; Liu, J.; Pang, Y.-P., Potent, easily synthesized huperzine A-tacrine hybrid acetylcholinesterase inhibitors. Bioorganic & Medicinal Chemistry Letters 1999,9, (16), 2335-2338.
52. Carlier PR, Du D, Han Y, et al. Dimerization of an inactive fragment of huperzine A produces a drug with twice the potency of natural porduct. Angew Chem Int Ed 2000,39,(10), 1775-1777.
53. Carlier PR, Han YF, Pang YP, et al. Preparation of dimeric quinolonyl amines related compounds as cholinesterase inhibitors GB: 2360518.
54. Jin GY, He XC, Zhang HY, et al. Synthesis of alkylene-linked dimers of (-)-huperzine A. Chinese Chemical Letters 2002, 13, (1), 23-26.
55. Jin Gy, Luo XM, He XC, et al. Synthesis and docking studies of alkylene-linked dimers of (-)-huperzine A. Arzneimittel-Forschung 2003, 53, (11), 753-757.
56. Feng, S.; Xia, Y.; Han, D.; Zheng, C; He, X.; Tang , X.; Bai, D., Synthesis and acetylcholinesterase inhibition of derivatives of huperzine B. Bioorganic & Medicinal Chemistry Letters 2005, 15, (3), 523-526.
57. Feng, S.; Wang, Z.; He, X.; Zheng, S.; Xia, Y.; Jiang, H.; Tang, X.; Bai, D.,Bis-huperzine B: Highly Potent and Selective Acetylcholinesterase Inhibitors. Journal of Medicinal Chemistry 2005,48, (3), 655-657.
58. He, X.-C.; Feng, S.; Wang, Z.-F.; Shi, Y.; Zheng, S.; Xia, Y.; Jiang, H.; Tang ,X.-c; Bai, D., Study on dual-site inhibitors of acetylcholinesterase: Highly potent derivatives of bis- and bifunctional huperzine B. Bioorganic & Medicinal Chemistry 2007,15,(3), 1394-1408.
59. Sauvaitre, T.; Barlier, M.; Herlem, D.; Gresh, N.; Chiaroni, A.; Guenard, D.;Guillou, C, New Potent Acetylcholinesterase Inhibitors in the Tetracyclic Triterpene Series. Journal of Medicinal Chemistry 2007, 50, (22), 5311-5323.
60. Kapkova, P.; Stiefl, N.; Suerig, U.; Engels, B.; Baumann, K.; Holzgrabe, U.,Synthesis, biological activity, and docking studies of new acetylcholinesterase inhibitors of the bispyridinium type. Archiv der Pharmazie (Weinheim, Germany) 2003, 336, (11), 523-540.
61. Alptuezuen, V.; Kapkova, P.; Baumann, K.; Erciyas, E.; Holzgrabe, U., Synthesis and biological activity of pyridinium-type acetylcholinesterase inhibitors. Journal of Pharmacy and Pharmacology 2003, 55, (10), 1397-1404.
62. Kapkova, P.; Alptuezuen, V.; Frey, P.; Erciyas, E.; Holzgrabe, U., Search for dual function inhibitors for Alzheimer's disease: Synthesis and biological activity of acetylcholinesterase inhibitors of pyridinium-type and their Aβ fibril formation inhibition capacity. Bioorganic & Medicinal Chemistry 2006,14, (2), 472-478.
63. Pietsch, M.; Guetschow, M., Synthesis of Tricyclic l,3-Oxazin-4-ones and Kinetic Analysis of Cholesterol Esterase and Acetylcholinesterase Inhibition. Journal of Medicinal Chemistry 2005,48, (26), 8270-8288.
64. Tang, H.; Ning, F.-X.; Wei, Y.-B.; Huang, S.-L.; Huang, Z.-S.; Chan, A. S.-C.; Gu,L.-Q., Derivatives of oxoisoaporphine alkaloids: A novel class of selective acetylcholinesterase inhibitors. Bioorganic & Medicinal Chemistry Letters 2007, 17,(13), 3765-3768.
65. Decker, M., Novel inhibitors of acetyl- and butyrylcholinesterase derived from the alkaloids dehydroevodiamine and rutaecarpine. European Journal of Medicinal Chemistry 2005,40, (3), 305-313.
66. Decker, M.; Krauth, F.; Lehmann, J., Novel tricyclic quinazolinimines and related tetracyclic nitrogen bridgehead compounds as cholinesterase inhibitors with selectivity towards butyrylcholinesterase. Bioorganic & Medicinal Chemistry 2006,14,(6), 1966-1977.
67. Decker, M., Homobivalent Quinazolinimines as Novel Nanomolar Inhibitors of Cholinesterases with Dirigible Selectivity toward Butyrylcholinesterase Journal of Medicinal Chemistry 2006,49, (18), 5411-5413.
68. Rosini, M.; Andrisano, V.; Bartolini, M.; Bolognesi, M. L.; Hrelia, P.; Minarini,A.; Tarozzi, A.; Melchiorre, C, Rational Approach To Discover Multipotent Anti-Alzheimer Drugs. Journal of Medicinal Chemistry 2005,48, (2), 360-363.
69. Srinivasan, V.; Pandi-Perumal, S. R.; Maestroni, G. J. M.; Esquifino, A. I.;Hardeland, R.; Cardinali, D. P., Role of melatonin in neurodegenerative diseases.Neurotoxicity Research 2005, 7, (4), 293-318.
70. Marco-Contelles, J.; Leon, R.; de Rios, C.; Guglietta, A.; Terencio, J.; Lopez, M.G; Garcia, A. G; Villarroya, M., Novel Multipotent Tacrine-Dihydropyridine Hybrids with Improved Acetylcholinesterase Inhibitory and Neuroprotective Activities as Potential Drugs for the Treatment of Alzheimer's Disease. Journal of Medicinal Chemistry 2006,49, (26), 7607-7610.
71. Elsinghorst, P. W.; Cieslik, J. S.; Mohr, K.; Trankle, C.; Gutschow, M., First Gallamine-Tacrine Hybrid: Design and Characterization at Cholinesterases and the M2 Muscarinic Receptor Journal of Medicinal Chemistry 2007, 50, (23), 5685-5695.
72. Blandina, P.; Goldfarb, J.; Green, J. P., Activation of a 5-HT3 receptor releases dopamine from rat striatal slice. European Journal of Pharmacology 1988, 155, (3),349-50.
73. Barnes, J. M.; Barnes, N. M.; Costall, B.; Naylor, R. J.; Tyers, M. B., 5-HT3 receptors mediate inhibition of acetylcholine release in cortical tissue. Nature (London, United Kingdom) 1989, 338, (6218), 762-3.
74. Cappelli, A.; Gallelli, A.; Manini, M.; Anzini, M.; Mennuni, L.; Makovec, F.;Menziani, M. C; Alcaro, S.; Ortuso, F.; Vomero, S., Further Studies on the Interaction of the 5-Hydroxytryptamine3 (5-HT3) Receptor with Arylpiperazine Ligands.Development of a New 5-HT3 Receptor Ligand Showing Potent Acetylcholinesterase Inhibitory Properties. Journal of Medicinal Chemistry 2005,48, (10), 3564-3575.
75. Piazzi, L.; Cavalli, A.; Colizzi, F.; Belluti, F.; Bartolini, M.; Mancini, F.;Recanatini, M.; Andrisano, V.; Rampa, A., Multi-target-directed coumarin derivatives:hAChE and BACE1 inhibitors as potential anti-Alzheimer compounds. Bioorganic & Medicinal Chemistry Letters 2008,18, (1), 423-426.
76. Toda, N.; Tago, K.; Marumoto, S.; Takami, K.; Ori, M.; Yamada, N.; Koyama, K.;Naruto, S.; Abe, K.; Yamazaki, R., Design, synthesis and structure-Activity relationships of dual inhibitors of acetylcholinesterase and serotonin transporter as potential agents for Alzheimer's disease. Bioorganic & Medicinal Chemistry 2003, 11,(9), 1935-1955.
77. Toda, N.; Tago, K.; Marumoto, S.; Takami, K.; Ori, M.; Yamada, N.; Koyama, K.;Naruto, S.; Abe, K., A conformational restriction approach to the development of dual inhibitors of acetylcholinesterase and serotonin transporter as potential agents for Alzheimer's disease. Bioorganic & Medicinal Chemistry 2003,11, (20), 4389-4415.
78. Sterling, J.; Herzig, Y.; Goren, T.; Finkelstein, N.; Lerner, D.; Goldenberg, W.,Novel Dual Inhibitors of AChE and MAO Derived from Hydroxy Aminoindan and Phenethylamine as Potential Treatment for Alzheimer's Disease. Journal of Medicinal Chemistry 2002,45, (24), 5260-5279.
79. Poltyrev, T.; Gorodetsky, E.; Bejar, C; Schorer-Apelbaum, D.; Weinstock. M.,Effect of chronic treatment with ladostigil (TV-3326) on anxiogenic and depressive-like behaviour and on activity of the hypothalamic-pituitary-adrenal axis in male and female prenatally stressed rats. Psychopharmacology (Berlin, Germany) 2005,181,(1), 118-125.
80. Sussman, J. L.; Harel, M.; Frolow, F.; Oefher, C; Goldman, A.; Toker, L.; Silman,I., Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein. Science (Washington, DC, United States) 1991, 253,(5022), 872-9.
81. De Ferrari, G. V.; Canales, M. A.; Shin, I.; Weiner, L. M.; Silman, I.; Inestrosa, N.C, A structural motif of acetylcholinesterase that promotes amyloid beta-peptide fibril formation. Biochemistry 2001,40, (35), 10447-10457.
82. Bartolini, M.; Bertucci, C; Cavrini, V.; Andrisano, V., beta.-Amyloid aggregation induced by human acetylcholinesterase:inhibition studies.Biochemical Pharmacology 2003,65,(3),407-416.
83.Giacobini,E.,Cholinesterases:New Roles in Brain Function and in Alzheimer's Disease.Neurochemical Research 2003,28,(3-4),515-522.
84.Pang,Y.-P.K.,A.,Prediction of the binding sites of huperzine A in acetylcholinesterase by docking studies,d.Comput-Aided Mol.Des.1994,(8),669-681.
85.Bose,N.K.;Chaudhury,D.N.,Isocoumarins.I.Preparation and cyclization of 2-carboxy-4,5-dimethoxyphenylacetaldehyde.J.lndian Chem.Soc.1965,42,(4),211-14.
86.Seed,A.J.;Sonpatki,V.;Herbert,M.R.,3-(4-bromobenzoyl)propanoic acid.Organic Syntheses 2002,79 204-208.
87.Guiso,M.;Bianco,A.;Marra,C.;Cavarischia,C.,One-pot synthesis of 6-hydroxyisochromans:The example of demethyl-oxa-coclaurine.European Journal of Organic Chemistry 2003,(17),3407-3411.
88.Ruchirawat,S.;Mutarapat,T.,An efficient synthesis of lamellarin alkaloids:synthesis of lamellarin G trimethyl ether.Tetrahedron Letters 2001,42,(6),1205-1208.
89.Tramontini,M.,Advances in the chemistry of Mannich bases.Synthesis 1973,(12),703-75.
90.陈芬儿.有机药物合成法 145 替米哌隆的合成
91.Sheng,R.;Lin,X.;Li,J.;Jiang,Y.;Shang,Z.;Hu,Y.,Design,synthesis,and evaluation of 2-phenoxy-indan-l-one derivatives as acetylcholinesterase inhibitors.Bioorganic & Medicinal Chemistry Letters 2005,15,(17),3834-3837.
92.Belluti,F.;Rampa,A.;Piazzi,L.;Bisi,A.;Gobbi,S.;Bartolini,M.;Andrisano,V.;Cavalli,A.;Recanatini,M.;Valenti,P.,Cholinesterase Inhibitors:Xanthostigrnine Derivatives Blocking the Acetylcholinesterase-Induced.beta.-Amyloid Aggregation.Journal of Medicinal Chemistry 2005,48,(13),4444-4456.
93.Recanatini,M.;Cavalli,A.;Belluti,F.;Piazzi,L.;Rampa,A.;Bisi,A.;Gobbi,S.;Valenti,P.;Andrisano,V.;Bartolini,M.;Cavrini,V.,SAR of 9-Amino-1,2,3,4-tetrahydroacridine-Based Acetylcholinesterase Inhibitors:Synthesis,Enzyme Inhibitory Activity,QSAR,and Structure-Based CoMFA of Tacrine Analogues.Journal of Medicinal Chemistry 2000,43,(10),2007-2018.
94.Wang,X.D.;Chen,X.Q.;Yang,H.H.;Hu,G.Y.,Comparison of the effects of cholinesterase inhibitors on[3H]MK-801 binding in rat cerebral cortex.Neuroscience letters 1999,272,(1),21-24.
95.Akasofu,S.;Kosasa,T.;Kimura,M.;Kubota,A.,Protective effect of Donepezil in a primary culture of rat cortical neurons exposed to oxygen-glucose deprivation.European Journal of Pharmacology 2003,472,(1-2),57-63.
96.早老性痴呆症的治疗药物盐酸多奈哌齐的开发应用,国外医药抗生素分册,2000,21(3):232-235。.
97.Sugimoto,H.O.,Hiroo;Arai,Yasuo;Iimura,Youichi;Yamanishi,Yoshiharu,Research and development of donepezil hydrochloride,a new type of acetylcholinesterase inhibitor.Japanese Journal of Pharmacology 2002,89,(1),7-20.
98.Barltrop,J.A.,Synthesis of analgesic substances.Journal of the Chemical Society,1946,958-65.
99.Koul,S.;Singh,B.;Taneja,S.C.;Qazi,G.N.,New chemo and chemo-enzymatic synthesis of β-benzyl-γ-butyrolactones.Tetrahedron 2003,59,(19),3487-3491.
100.Yi,C.S.;Martinelli,L.C.;Blanton,C.D.,Jr.,Synthesis of N-methyl-1-oxa-5-aza[10]paracyclophane:a conformationally restricted analog of phenoxypropylamines.Journal of Organic Chemistry 1978,43,(3),405-9.
101.Zheng,H.;Gao,W.;Ji,X.;Zhang,S.,Improved method for synthesis of Tyrosol.Zhongguo Yaowu Huaxue Zazhi 2002,12,(3),166-167.
102.Holshouser,M.H.;Kolb,M.,Facile synthesis of glycol metabolites of phenethylamine drugs Journal of Pharmaceutical Sciences 1986,75,(6),619-21.
103.Psiorz,M.;Heider,J.;Bombard,A.;Hauel,N.;Noll,K.;Narr,B.;Lillie,C.;Kobinger,W.;Daemmgen,J.Preparation,formulation,and testing of tetrahydronaphthalene and indan derivatives as bradycardic agents.DE 3630903,1988.
104.Srinivasa,G.R.;Abiraj,K.;Gowda,D.C.,Polymer-supported formate and zinc:a novel system for the transfer hydrogenation of aromatic nitro compounds.lndian Journal of Chemistry,Section B:Organic Chemistry Including Medicinal Chemistry 2006,45B,(1),297-301.
105.Ohta,S.;Okamoto,M.,Synthesis of carbonyl compounds via biogenetic-type transamination reaction Synthesis 1982,(9),756-8.
106.Wang,R.;Guan,Y.,Selective reductive alkylation of secondary amines with carbonyl compounds.Gaodeng Xuexiao Huaxue Xuebao 1990,11,(8),894-6.
107.Jacob,J.N.;Nichols,D.E.;Kohli,J.D.;Glock,D.,Dopamine agonist properties of N-alkyl-4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinolines.Journal of Medicinal Chemistry.1981,24,(8),1013-15.
108.Recanatini,M.;Cavalli,A.;Belluti,F.;Piazzi,L.;Rampa,A.;Bisi,A.;Gobbi,S.;Valenti,P.;Andrisano,V.;Bartolini,M.;Cavrini,V.,SAR of 9-Amino-l,2,3,4-tetrahydroacridine-Based Acetylcholinesterase Inhibitors:Synthesis,Enzyme Inhibitory Activity,QSAR,and Structure-Based CoMFA of Tacrine Analogues.Journal of Medicinal Chemistry 2000,43,(10),2007-2018.
109.Li,J.-r.;Han,F.-b.;Yang,X.-h.;Li,W.-t.;Ma,S.-I.,Syntheses and characterizations of tacrine and its derivatives.Hecheng Huaxue 2005,13,(2),160-162.
110.Gilgun-Sherki,Y.;Melamed,E.;Often,D.,Antioxidant treatment in Alzheimer's disease:Current state.Journal of Molecular Neuroscience 2003,21,(1),1-11.
111.Knowles,M.;Kingsport,T.;Rochester,N.Process for production of 2,4,5-trihydroxy-acetophenone.US:2763691.
112.Xi,F.;Liang,X.;Lu,Y.,A new synthetic method for some 2-hydroxy-4,5-dialkoxy-acetophenones.Huaxue Shiji 1990,12,(5),299-312.
113.Correa,R.;Pereira,M.A.S.;Buffon,D.;Dos Santos,L.;Cechinel Filho,V.;Santos,A.R.S.;Nunes,R.J.,Antinociceptive properties of chalcones.Structure-activity relationships.Archiv der Pharmazie 2001,334,(10),332-334..
114.Xiao,L.;Tan,W.;Li,Y.,First total synthesis of 0-kenusanone B.Synthetic Communications 1998,28,(15),2861-2869.
115.Mitsunobu,O.,The use of diethyl azodicarboxylate and triphenylphosphine in synthesis and transformation of natural products. Synthesis 1981, (1), 1-28..
116.Miko, T.; Ligneau, X.; Pertz, H. H.; Ganellin, C. R.; Arrang, J.-M.; Schwartz,J.-C; Schunack, W.; Stark, H., Novel Nonimidazole Histamine H3 Receptor Antagonists: l-(4-(Phenoxymethyl)benzyl)piperidines and Related Compounds.Journal of Medicinal Chemistry 2003,46, (8), 1523-1530.
117.Mavel, S.; Dikic, B.; Palakas, S.; Emond, P.; Greguric, I.; Gomez de Gracia, A.;Mattner, F.; Garrigos, M., Synthesis and biological evaluation of a series of flavone derivatives as potential radioligands for imaging the multidrug resistance-associated protein 1 (ABCC1/MRP1) Bioorganic & Medicinal Chemistry 2006, 14, (5),1599-1607.
118.Tsukayama, M.; Wada, H.; Kawamura, Y.; Yamashita, K.; Nishiuchi, M.,Regioselective synthesis of 6-alkyl- and 6-prenylpolyhydroxyisoflavones and 6-alkylcoumaronochromone derivatives. Chemical & Pharmaceutical Bulletin 2004,52,(11), 1285-1289.
119.Kawamura, Y.; Maruyama, M.; Tokuoka, T.; Tsukayama, M., Synthesis of isoflavones from 2'-hydroxychalcones using poly[4-(diacetoxy)iodo]styrene or related hypervalent iodine reagent. Synthesis 2002, (17), 2490-2496.
120. Doucet-Personeni, C; Bentley, P. D.; Fletcher, R. J.; Kinkaid, A.; Kryger, G.;Pirard, B.; Taylor, A., A Structure-Based Design Approach to the Development of Novel, Reversible AChE Inhibitors. Journal of Medicinal Chemistry 2001, 44, (20),3203-3215.
121. Diouf, O.; Depreux, P.; Chavatte, P.; Poupaert, J. H., Synthesis and preliminary pharmacological results on new naphthalene derivatives as 5-HT4 receptor ligands. European Journal of Medicinal Chemistry 2000, 35, (7 & 8),699-706.