Acetylcholinesterase inhibitors for potential use in Alzheimer's disease: molecular modeling, synthesis and kinetic evaluation of 11 H -indeno-[1,2- b ]-quinolin-10-ylamine derivatives

Rampa, Angela; Bisi, Alessandra; Belluti, Federica; Gobbi, Silvia; Valenti, Piero; Andrisano, Vincenza; Cavrini, Vanni; Cavalli, Andrea; Recanatini, Maurizio

doi:10.1016/s0968-0896(99)00306-5

Cited by 89 publications

(68 citation statements)

References 23 publications

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“…Since the paper of Steinberg et al on noncovalent AChE inhibitors related to 9-amino-1,2,3,4-tetrahydroacridine, 7 only few articles have been published dealing with structural modifications of tacrine [8][9][10][11][12][13]15 or with bis-tetrahydroacridine derivatives. 5 In our comparative QSAR paper published in 1997, 14 we pointed Figure 2.…”

Section: Discussionmentioning

confidence: 99%

SAR of 9-Amino-1,2,3,4-tetrahydroacridine-Based Acetylcholinesterase Inhibitors: Synthesis, Enzyme Inhibitory Activity, QSAR, and Structure-Based CoMFA of Tacrine Analogues

et al. 2000

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In this study, we attempted to derive a comprehensive SAR picture for the class of acetylcholinesterase (AChE) inhibitors related to tacrine, a drug currently in use for the treatment of the Alzheimer's disease. To this aim, we synthesized and tested a series of 9-amino-1,2,3,4-tetrahydroacridine derivatives substituted in the positions 6 and 7 of the acridine nucleus and bearing selected groups on the 9-amino function. By means of the Hansch approach, QSAR equations were obtained, quantitatively accounting for both the detrimental steric effect of substituents in position 7 and the favorable electron-attracting effect exerted by substituents in positions 6 and 7 of the 9-amino-1,2,3,4-tetrahydroacridine derivatives. The three-dimensional (3D) properties of the inhibitors were taken into consideration by performing a CoMFA analysis on the series of AChE inhibitors made by 12 9-amino-1,2,3, 4-tetrahydroacridines and 13 11H-indeno[1,2-b]quinolin-10-ylamines previously developed in our laboratory. The alignment of the molecules to be submitted to the CoMFA procedure was carried out by taking advantage of docking models calculated for the interactions of both the unsubstituted 9-amino-1,2,3,4-tetrahydroacridine and 11H-indeno[1,2-b]quinolin-10-ylamine with the target enzyme. A highly significant CoMFA model was obtained using the steric field alone, and the features of such a 3D QSAR model were compared with the classical QSAR equations previously calculated. The two models appeared consistent, the main aspects they had in common being (a) the individuation of the strongly negative contribution of the substituents in position 7 of tacrine and (b) a tentative assignment of the hydrophobic character to the favorable effect exerted by the substituents in position 6. Finally, a new previously unreported tacrine derivative designed on the basis of both the classical and the 3D QSAR equations was synthesized and kinetically evaluated, to test the predictive ability of the QSAR models. The 6-bromo-9-amino-1,2,3,4-tetrahydroacridine was predicted to have a pIC(50) value of 7.31 by the classical QSAR model and 7.40 by the CoMFA model, while its experimental IC(50) value was equal to 0.066 (+/-0.009) microM, corresponding to a pIC(50) of 7.18, showing a reasonable agreement between predicted and observed AChE inhibition data.

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Section: Discussionmentioning

confidence: 99%

SAR of 9-Amino-1,2,3,4-tetrahydroacridine-Based Acetylcholinesterase Inhibitors: Synthesis, Enzyme Inhibitory Activity, QSAR, and Structure-Based CoMFA of Tacrine Analogues

et al. 2000

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“…The majority of these compounds are soluble only in an organic solvent, which frequently requires a great number of controls to evaluate the effect per se of the solvent on enzyme activity. Thus, the use of alcohol methyl (14,15) alcohol ethyl (16), propylene glycol (17,18) and DMSO (11) sometimes are the only forms to prepare such compounds for biologic assessment.…”

Section: Introductionmentioning

confidence: 99%

Effects per se of Organic Solvents in the Cerebral Acetylcholinesterase of Rats

et al. 2005

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Acetylcholinesterase (AChE) was studied in different rat brain regions (cerebellum, hypothalamus, striatum, hippocampus and cortex) in the presence of different organic solvents normally used in the in vitro assay. The organic solvents used were acetone (C3H6O), acetonitrile (C2H3N), ethyl alcohol (C2H6O), isopropyl alcohol (C3H8O), methyl alcohol (CH4O), tert-butyl alcohol (C4H10O) and dimethyl sulfoxide (DMSO, C2H6OS) ranging from 0.6 to 10%. Ethyl and methyl alcohol presented no effect on AChE activity at any of the concentrations and brain structures tested. In the hippocampus, isopropyl alcohol did not demonstrate a significant inhibitory effect, even at high concentrations. Tert-butyl alcohol presented an interesting result, increased AChE activity (P < .05) in the hypothalamus (1.8%), cortex (1.8 and 2.5) and striatum (1.2, 1.8 and 2.5%) and decreased activity at a concentration of 10% in the cortex (P < .05) and striatum (P < .01). Acetone and acetonitrile presented similar results, both significantly inhibiting AChE in all structures (5%, P < .05 and 10%, P < .01). DMSO exhibited a highly inhibitory effect at practically all concentrations tested (P < .01). In conclusion, for testing new compounds on AChE activity in vitro, methyl and ethyl alcohol may be the best organic solvent choice.

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“…22 The graphical analysis of steady-state HuAChE inhibition data for 4 in comparison to donepezil is shown in Figure 2, whereas estimates of K i and IC 50 values are reported in Table 1 along with the corresponding values for donepezil. From the kinetic analysis, we concluded that both compounds caused a mixed type of inhibition, implying binding at both the catalytic and the peripheral sites of AChE.…”

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3-(4-{[Benzyl(methyl)amino]methyl}phenyl)-6,7-dimethoxy-2H-2-chromenone (AP2238) Inhibits Both Acetylcholinesterase and Acetylcholinesterase-Induced β-Amyloid Aggregation: A Dual Function Lead for Alzheimer's Disease Therapy

et al. 2003

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In recent years, the investigation of acetylcholinesterase (AChE) inhibitors has gained further interest, because the involvement of the peripheral site of the enzyme in the beta-amyloid (Abeta) aggregation process has been disclosed. We present here, for the first time, a direct evidence of the Abeta antiaggregating action of an AChE inhibitor (AP2238) purposely designed to bind at both the catalytic and the peripheral sites of the human enzyme.

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Acetylcholinesterase inhibitors for potential use in Alzheimer's disease: molecular modeling, synthesis and kinetic evaluation of 11 H -indeno-[1,2- b ]-quinolin-10-ylamine derivatives

Cited by 89 publications

References 23 publications

SAR of 9-Amino-1,2,3,4-tetrahydroacridine-Based Acetylcholinesterase Inhibitors: Synthesis, Enzyme Inhibitory Activity, QSAR, and Structure-Based CoMFA of Tacrine Analogues

SAR of 9-Amino-1,2,3,4-tetrahydroacridine-Based Acetylcholinesterase Inhibitors: Synthesis, Enzyme Inhibitory Activity, QSAR, and Structure-Based CoMFA of Tacrine Analogues

Effects per se of Organic Solvents in the Cerebral Acetylcholinesterase of Rats

3-(4-{[Benzyl(methyl)amino]methyl}phenyl)-6,7-dimethoxy-2H-2-chromenone (AP2238) Inhibits Both Acetylcholinesterase and Acetylcholinesterase-Induced β-Amyloid Aggregation: A Dual Function Lead for Alzheimer's Disease Therapy

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