Novel Anti-Alzheimer's Dimer Bis(7)-Cognitin: Cellular and Molecular Mechanisms of Neuroprotection Through Multiple Targets

Li, Wenming; Mak, Marvin; Jiang, Hualiang; Wang, Qinwen; Pang, Yuan Ping; Chen, Kaixian; Han, Yifan

doi:10.1016/j.nurt.2008.10.040

Cited by 55 publications

(52 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The 5-HT6 receptor antagonist idalopirdine, in combination with a cholinesterase inhibitor, may also increase cognitive function [325] . Huperzine A [326,327] , 2,2',4'-trihydroxychalcone (TDC) [328] and bis(7)-cognitin [329] exhibit neuroprotective effects. Agenin [330] and clioquinol [331] can inhibit Aβ deposition.…”

Section: Therapies Directed Against the Tau Proteinmentioning

confidence: 99%

Amyloid beta: structure, biology and structure-based therapeutic development

et al. 2017

View full text Add to dashboard Cite

Amyloid beta peptide (Aβ) is produced through the proteolytic processing of a transmembrane protein, amyloid precursor protein (APP), by β-and γ-secretases. Aβ accumulation in the brain is proposed to be an early toxic event in the pathogenesis of Alzheimer's disease, which is the most common form of dementia associated with plaques and tangles in the brain. Currently, it is unclear what the physiological and pathological forms of Aβ are and by what mechanism Aβ causes dementia. Moreover, there are no efficient drugs to stop or reverse the progression of Alzheimer's disease. In this paper, we review the structures, biological functions, and neurotoxicity role of Aβ. We also discuss the potential receptors that interact with Aβ and mediate Aβ intake, clearance, and metabolism. Additionally, we summarize the therapeutic developments and recent advances of different strategies for treating Alzheimer's disease. Finally, we will report on the progress in searching for novel, potentially effective agents as well as selected promising strategies for the treatment of Alzheimer's disease. These prospects include agents acting on Aβ, its receptors and tau protein, such as small molecules, vaccines and antibodies against Aβ; inhibitors or modulators of β-and γ-secretase; Aβ-degrading proteases; tau protein inhibitors and vaccines; amyloid dyes and microRNAs.

show abstract

Section: Therapies Directed Against the Tau Proteinmentioning

confidence: 99%

Amyloid beta: structure, biology and structure-based therapeutic development

et al. 2017

View full text Add to dashboard Cite

show abstract

“…The syntheses of pyridonepezils 14−17 (Chart 1) have been carried out by N-alkylation of readily available ethyl 6-chloro-5-cyano-2-methyl-4-phenylnicotinate (22) 41 with commercial 4-amino-1-benzylpiperidine (23), (1-benzylpiperidin-4-yl)-methanamine (24), 42 2-(1-benzylpiperidin-4-yl)ethanamine (25), 42 and 3-(1-benzylpiperidin-4-yl)propan-1-amine (26) 43 in high yield (Scheme 1).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Synthesis, Pharmacological Assessment, and Molecular Modeling of Acetylcholinesterase/Butyrylcholinesterase Inhibitors: Effect against Amyloid-β-Induced Neurotoxicity

Silva

Chioua

Samadi

et al. 2013

ACS Chem. Neurosci.

View full text Add to dashboard Cite

ABSTRACT:The synthesis, molecular modeling, and pharmacological analysis of phenoxyalkylamino-4-phenylnicotinates (2−7), phenoxyalkoxybenzylidenemalononitriles (12, 13), pyridonepezils (14−18), and quinolinodonepezils (19−21) are described. Pyridonepezils 15−18 were found to be selective and moderately potent regarding the inhibition of hAChE, whereas quinolinodonepezils 19−21 were found to be poor inhibitors of hAChE. The most potent and selective hAChE inhibitor was ethyl 6-(4-(1-benzylpiperidin-4-yl)butylamino)-5-cyano-2-methyl-4-phenylnicotinate (18) [IC 50 (hAChE) = 0.25 ± 0.02 μM]. Pyridonepezils 15−18 and quinolinodonepezils 20−21 are more potent selective inhibitors of EeAChE than hAChE. The most potent and selective EeAChE inhibitor was ethyl 6-(2-(1-benzylpiperidin-4-yl)ethylamino)-5-cyano-2-methyl-4-phenylnicotinate (16) [IC 50 (EeAChE) = 0.0167 ± 0.0002 μM], which exhibits the same inhibitory potency as donepezil against hAChE. Compounds 2, 7, 13, 17, 18, 35, and 36 significantly prevented the decrease in cell viability caused by Aβ 1−42 . All compounds were effective in preventing the enhancement of AChE activity induced by Aβ 1−42 . Compounds 2−7 caused a significant reduction whereas pyridonepezils 17 and 18, and compound 16 also showed some activity . The pyrazolo [3,4-b]quinolines 36 and 38 also prevented the upregulation of AChE induced by Aβ 1−42 . Compounds 2, 7, 12, 13, 17, 18, and 36 may act as antagonists of voltage sensitive calcium channels, since they significantly prevented the Ca 2+ influx evoked by KCl depolarization. Docking studies show that compounds 16 and 18 adopted different orientations and conformations inside the active-site gorges of hAChE and hBuChE. The structural and energetic features of the 16-AChE and 18-AChE complexes compared to the 16-BuChE and 18-BuChE complexes account for a higher affinity of the ligand toward AChE. The present data indicate that compounds 2, 7, 17, 18, and 36 may represent attractive multipotent molecules for the potential treatment of Alzheimer's disease.

show abstract

“…[9][10][11][12] However, as AD progresses, the activity of AChE decreases, while that of BuChE significantly increases and may even surpass the AChE activity. 13,14 The acetylcholine binding site of AChE is located at the base of a deep hydrophobic channel measuring approximately 20 Å in length. It is formed by a catalytic anionic site (CAS) composed by the catalytic triad Ser200, His440 and Glu327 and the anionic subsite which is defined by Trp84, Tyr130, Tyr330, and Phe331 amino acid residues.…”

Section: Introductionmentioning

confidence: 99%

“…41 In the binding mode observed for the dimer, a THA component is located at the CAS region, close to the enzyme catalytic triad, while the other THA component binds to PAS at the entrance of the catalytic gorge. 42 After Pang et al 14 first report, several examples of homo-or hetero-dimeric cholinesterase inhibitors (ChEIs), containing units of tacrine linked by an oligomethylene chain, have appeared in the literature. 43 In June 2016, Schmidt et al 44 synthesized mono-and dimeric tacrine derivatives with different substitution patterns of tacrine moiety and linker lengths combining a set of substituents at aromatic region (a) and the alicyclic region (d).…”

Section: Introductionmentioning

confidence: 99%

“…38 The authors found that methylene chain spacers joining two units of tacrine moiety allowed a double interaction of the compound with the enzyme by binding simultaneously to the CAS and PAS. 14,[38][39][40] These results lead the authors to perform the synthesis of alkylene-linked bis-tacrine compounds (Figure 1). 40 Among the compounds obtained, the heptylene-linked bis-tacrine (2), also called bis(7)-cognitin or bis(7)-tacrine was found to be almost fifteen hundred times more potent against AChE than tacrine.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Chiral Bistacrine Analogues: Synthesis, Cholinesterase Inhibitory Activity and a Molecular Modeling Approach

Lopes¹,

Costa²,

Ceschi³

et al. 2017

J. Braz. Chem. Soc.

View full text Add to dashboard Cite

Cholinesterase enzymes are important targets for the therapy of Alzheimer's disease. Tacrine-based dual binding site cholinesterases inhibitors are potential disease-modifying anti-Alzheimer drug candidates. In the present work, we described the synthesis of a series of chiral homo-and heterodimers of bis (7)-tacrine connected by a heptylene chain as a spacer with the methyl substituent at the C-3 position of the alicyclic region of tacrine nucleus and/or a chlorine atom attached to the C-6. Friedländer cyclocondensation between (R) or (S) 3-methylcyclohexanone prepared from monoterpene pulegone and o-aminobenzoic acids in the presence of POCl 3 afford 9-chloroacridines as intermediates, which were used to the synthesis of homo-and heterodimers. All compounds demonstrated to be potent inhibitors of acetylcholinesterase (AChE) at low nanomolar concentration and showed selectivity for AChE over butyrylcholinesterase (BuChE). Furthermore, the affinity difference between enantiomeric bis(7)-tacrine analogues series indicated some degree of stereoselectivity in the active site of AChE for chiral bis-cognitin compounds. Keywords: bistacrine, chiral, cholinesterases, synthesis, molecular docking IntroductionAlzheimer's disease (AD) is one of the leading causes of death among elderly people in the World, and its treatment remains a challenge for the pharmaceutical community. Nearly a million new cases per year it is expected to emerge by 2050.1,2 The proposed cholinergic hypothesis of cognitive impairment has been accepted for decades to explain AD and is characterized by the loss of cholinergic basal forebrain, and their projections to the cerebral cortices. 2,3 According to this hypothesis, the memory and cognitive decline well-marked in AD result from a deficit of the important neurotransmitter acetylcholine (ACh). In this context, the inhibition of cholinesterase enzymes (ChEs) that are responsible for the hydrolyses of ACh emerge as a symptomatic treatment to relieve these symptoms. [4][5][6] The current therapeutic options for AD are limited to three inhibitors of acetylcholinesterase (AChEI):4-8 donepezil (Aricept ® ), rivastigmine (Exelon ® ) and galantamine (Razadyne ® , Reminyl ® ). In addition, the N-methyl-D-aspartate (NMDA) receptor antagonist memantine (Namenda ® ) is also used. [9][10][11] However, none of these therapeutic options represent a real cure.The cholinesterase enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are enzymes which are found in the central nervous system (CNS) and catalyze the hydrolysis of ACh efficiently but at different rates. [9][10][11][12] However, as AD progresses, the activity of AChE decreases, while that of BuChE significantly increases and may even surpass the AChE activity. 13,14 The acetylcholine binding site of AChE is located at the base of a deep hydrophobic channel measuring Lopes et al. 2219 Vol. 28, No. 11, 2017 approximately 20 Å in length. It is formed by a catalytic anionic site (CAS) composed by the catalytic triad Ser200, His440 and Gl...

show abstract

Novel Anti-Alzheimer's Dimer Bis(7)-Cognitin: Cellular and Molecular Mechanisms of Neuroprotection Through Multiple Targets

Cited by 55 publications

References 50 publications

Amyloid beta: structure, biology and structure-based therapeutic development

Amyloid beta: structure, biology and structure-based therapeutic development

Synthesis, Pharmacological Assessment, and Molecular Modeling of Acetylcholinesterase/Butyrylcholinesterase Inhibitors: Effect against Amyloid-β-Induced Neurotoxicity

Chiral Bistacrine Analogues: Synthesis, Cholinesterase Inhibitory Activity and a Molecular Modeling Approach

Contact Info

Product

Resources

About