Synthesis and acetylcholinesterase/butyrylcholinesterase inhibition activity of 4-amino-2, 3-diaryl-5, 6, 7, 8-tetrahydrofuro(and thieno)[2, 3-b]-quinolines,and 4-amino-5, 6, 7, 8, 9-pentahydro-2, 3-diphenylcyclohepta[e]furo(and thieno)-[2, 3-b]pyridines

The acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition activities of a series of 4-amino-2, 3-diaryl-5, 6, 7, 8-tetrahydrofuro[2, 3-b]quinolines (10-12)/4-amino-5, 6, 7, 8-tetrahydro-2, 3-diphenylthieno[2, 3-b]quinoline (14) and 4-amino-5, 6, 7, 8, 9-pentahydro-2, 3-diphenylcyclohepta[e]furo[2, 3-b]pyridine (13)/4-amino-5, 6, 7, 8, 9-pentahydro-2, 3-phenylcyclohepta[e]thieno[2, 3-b]pyridine (15) are described. These compounds are tacrine (THA) analogues which have been prepared either from readily available 2-amino-3-cyano-4, 5-diarylfurans (16-18) or from 2-amino-3-cyano-4, 5-diphenylthiophene (19), via Friedl?nder condensation with cyclohexanone or cycloheptanone. These compounds are competitive inhibitors for acetylcholinesterase, the more potent being compound (13) which is three-fold less active than tacrine. The butyrylcholinesterase inhibition activity is significant only in compounds 10 and133, which are ten-fold less active than tacrine. It is found that the products 11 and 12 strongly inhibit acetylcholinesterase, and show excellent selectivity regarding butyrylcholinesterase.     

New tacrine-hydrazinonicotinamide hybrids as acetylcholinesterase inhibitors of potential interest for the early diagnostics of Alzheimer's disease

The syntheses and the preliminary results of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition by an affinity series of tacrine-hydrazinonicotinamide hybrids are described. These molecules were prepared by condensation of tacrine analogues with the hydrazine nicotinate moiety (HYNIC). Derivatives 6a and 6b showed lower activity than the model tacrine, while compounds 6c and 6d showed the strongest affinity to AChE. All the tested compounds exhibited lower affinity for BChE than tacrine. Alzheimer disease (AD) is characterised by a deficit of acetylcholinesterase, and these new compounds, as ligands for 99mTc complexes, are potential radiopharmaceuticals for an early diagnosis of Alzheimer's disease.     

他克林衍生物及其类似物的研究进展

他克林是一个选择性较好但毒副作用明显的乙酷胆碱酯酶抑制剂。为了克服其不足，许多他克林衍生物和类似物都已被合成并进行了药理研究。从他克林的芳环、脂环和侧链氨基等3个方面对他克林衍生物及类似物的合成和药理研究进行综述。     

Design, synthesis and biological evaluation of new 2-benzoxazolinone derivatives as potential cholinesterase inhibitors for therapy of alzheimer's disease

Currently acetylcholinesterase inhibitor (AChEI) therapy is one of the most frequently used methods in the treatment of Alzheimer's disease; tacrine, donepezil, rivastygmine and galantamine are applied in different stages of AD. In the present study, we propose a new series of 2-benzoxazolinone derivatives as potential cholinesterase inhibitors. These compounds were synthesized by condensation of 6-chloro acetyl-2-benzoxa zolinone with the corresponding amine and evaluated as acetylcholinesterase inhibitors using the colorimetric Ellman's method. Selectivity and the IC50 values were determined for the received derivatives. All tested compounds exhibited the inhibitory activity towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Compound 3e showed stronger activity than the standard tacrine, and compound 3a showed activity similar to that of tacrine for AChE. Compounds 3a, 3b, 3c, and 3e showed stronger activity than the standard donepezil towards the inhibition of BChE, and the compound 3e showed stronger activity than donepezil towards AChE.     

Qsar for Acetylcholinesterase and Butyrylcholinesterase Inhibition by Cardiovascular Drugs and Benzodiazepines

Five common cardiovascular drugs, lovastatin, simvastatin, amlodipine besylate, nifedipine, and hydralazine hydrochloride, and two common benzodiazepines, diazepam and chlordiazepoxide hydrochloride, are all reversible mixed-type inhibitors of acetylcholinesterase and butyrylcholinesterase. The pK_i values for acetylcholinesterase and butyrylcholinesterase inhibitions by these drugs are linearly correlated with the molecular weights, with slopes of 0.005 and 0.0021, respectively. Therefore, van der Waals’ interactions between acetylcholinesterase and these drugs are stronger than those between butyrylcholinesterase probably due to a small active site gorge and a significant peripheral anionic site for acetylcholinesterase. The fact that the pK_i values for both butyrylcholinesterase and acetylcholinesterase inhibitions are linearly correlated with each other suggests that both enzyme inhibitions proceed via a common mechanism. Furthermore, acetylcholinesterase and butyrylcholinesterase inhibitors such as tacrine, donepezil, rivastigmine, and galantamine are currently used to manage Alzheimer’s disease. Since amlodipine besylate is a very potent inhibitor of both cholinesterases, amlodipine besylate may, like donepezil, be useful in Alzheimer’s disease treatment.     

石杉碱乙的抗胆碱酯酶作用

目的：测试石杉碱乙的抗胆碱酯酶作用并与他克林进行比较,方法：比色法用于测定胆碱酶活性。结果：石杉碱乙和他克林对ＢｕＣｈＥ和ＡＣｈＥ抑制的ＩＣ５０值的比率分别为６５．８和０．５４,石杉碱乙对乙酰胆碱酯酶有更强的选择性抑制作用。石杉碱乙灌胃对脑内ＡＣｈＥ的抑制作用明业强于他克林,而他克林对ＢｕＣｈＥ的抑制作用强于石杉碱乙,并有严重副反应,单次灌胃石杉碱乙在４小时内对脑内ＡＣｈＥ产生较对稳定的抑制作用,     

A comparative study in rats of the in vitro and in vivo pharmacology of the acetylcholinesterase inhibitors tacrine, donepezil and NXX-066

The in vitro and in vivo effects of the novel acetylcholinesterase inhibitors donepezil and NXX-066 have been compared to tacrine. Using purified acetylcholinesterase from electric eel both tacrine and donepezil were shown to be reversible mixed type inhibitors, binding to a similar site on the enzyme. In contrast, NXX-066 was an irreversible non-competitive inhibitor. All three compounds were potent inhibitors of rat brain acetylcholinesterase (IC50 [nM]; tacrine: 125 +/- 23; NXX-066: 148 +/- 15; donepezil: 33 +/- 12). Tacrine was also a potent butyrylcholinesterase inhibitor. Donepezil and tacrine displaced [3H]pirenzepine binding in rat brain homogenates (IC50 values [microM]; tacrine: 0.7; donepezil: 0.5) but NXX-066 was around 80 times less potent at this M1-muscarinic site. Studies of carbachol stimulated increases in [Ca2+]i in neuroblastoma cells demonstrated that both donepezil and tacrine were M1 antagonists. Ligand binding suggested little activity of likely pharmacological significance with any of the drugs at other neurotransmitter sites. Intraperitoneal administration of the compounds to rats produced dose dependent increases in salivation and tremor (ED50 [micromol/kg]; tacrine: 15, NXX-066: 35, donepezil: 6) with NXX-066 having the most sustained effect on tremor. Following oral administration, NXX-066 had the slowest onset but the greatest duration of action. The relative potency also changed, tacrine having low potency (ED50 [micromol/kg]; tacrine: 200, NXX-066: 30, donepezil: 50). Salivation was severe only in tacrine treated animals. Using in vivo microdialysis in cerebral cortex, both NXX-066 and tacrine were found to produce a marked (at least 30-fold) increase in extracellular acetylcholine which remained elevated for more than 2 h after tacrine and 4 h after NXX-066.     

Homodimeric tacrine congeners as acetylcholinesterase inhibitors

In the search for highly selective and potent derivatives of tacrine (1a), a number of homodimeric tacrine congeners were synthesized and conducted for their effects on rat acetylcholinesterase (AChE) and human butyrylcholinesterase (BChE) inhibitions. Heptylene-linked bis-(6-chloro)tacrine (3h) was found up to 3000- and 3-fold more potent in inhibiting rat AChE than tacrine and the unsubstituted bis-tacrine 3b, respectively. Changes in the size of the carbocyclic ring of the dimeric tacrine reduced both the selectivity and the potency of AChE inhibition as compared to 3b. Inserting an aza into the tacrine nucleus as the desired isosteres 3j-m resulted in moderate potency but tended to be detrimental to selectivity. The pronounced enhancement of AChE inhibition potency and AChE/BChE selectivity was achieved with incorporation of a halogen at the 6-position of homodimeric tacrines. The assay results of 3a-m also provided evidence that the 7-methylene tether tended to be optimal to AChE inhibition potency.     

Multiple enzyme inhibitions by histamine H3 receptor antagonists as potential procognitive agents

Novel highly affine histamine H3 receptor ligands with additional inhibitory effects on the main histamine metabolizing enzyme in the brain, N-methyltransferase, chemically show structural elements of the acetylcholinesterase inhibitor tacrine. H3 receptor antagonism, inhibition of metabolisation of neuronal histamine as well as inhibition of hydrolysis of acetylcholine are each one believed to improve reduced cognitive functions, which is useful for symptomatic treatment of Alzheimer's disease. Some of the new compounds proved in a slightly modified colorimetric Ellmann's assay to be potent inhibitors of acetylcholinesterase and of butyrylcholinesterase which is another catalytic enzyme hydrolysing acetylcholine. Some compounds with (sub)nanomolar activities on the histamine-related targets are also active in the nanomolar concentration range on both cholinesterase targets being 5- to 40-times more potent than tacrine. Preliminary structure-activity relationships could already be drawn from the small number of compounds. The compounds acting as hybrid drugs simultaneously on four different targets to enhance cognitive functions via different pathways are promising lead structures for a new approach in the treatment of Alzheimer's disease.     

Synthesis and pharmacological evaluation of huprine-tacrine heterodimers: subnanomolar dual binding site acetylcholinesterase inhibitors

A series of huprine-tacrine heterodimers has been developed by connection of huprine Y, a compound with one of the highest affinities for the active site of acetylcholinesterase yet reported, with tacrine, a compound with known affinity for the peripheral site of the enzyme, through a linker of appropriate length to allow simultaneous interaction with both binding sites. These compounds exhibit human acetylcholinesterase and butyrylcholinesterase inhibitory activities with IC(50) values in the subnanomolar and low nanomolar range, respectively.     

Novel heterobivalent tacrine derivatives as cholinesterase inhibitors with notable selectivity toward butyrylcholinesterase

Two series of novel heterobivalent tacrine derivatives were synthesized. A trimethoxy substituted benzene was linked to the tacrine moiety by a hydrazide-based linker. The compounds were evaluated as cholinesterase inhibitors, and trimethoxybenzoic acid derivatives with 11- or 12-atom spacers were the most potent inhibitors of human acetylcholinesterase. The inhibitors showed a surprising selectivity toward human butyrylcholinesterase, where several trimethoxyphenylpropionic acid derivatives had IC(50) values less than 250 pM.     

Cholinesterase inhibitors used in the treatment of Alzheimer's disease: the relationship between pharmacological effects and clinical efficacy

The deficiency in cholinergic neurotransmission in Alzheimer's disease has led to the development of cholinesterase inhibitors as the first-line treatment for symptoms of this disease. The clinical benefits of these agents include improvements, stabilisation or less than expected decline in cognition, function and behaviour. The common mechanism of action underlying this class of agents is an increase in available acetylcholine through inhibition of the catabolic enzyme, acetylcholinesterase. There is substantial evidence that the cholinesterase inhibitors, including donepezil, galantamine and rivastigmine, decrease acetylcholinesterase activity in a number of brain regions in patients with Alzheimer's disease. There is also a significant correlation between acetylcholinesterase inhibition and observed cognitive improvement. However, the cholinesterase inhibitors are reported to have additional pharmacological actions. Rivastigmine inhibits butyrylcholinesterase with a similar affinity to acetylcholinesterase, although it is not clear whether the inhibition of butyrylcholinesterase contributes to the therapeutic effect of rivastigmine. Based on data from preclinical studies, it has been proposed that galantamine also potentiates the action of acetylcholine on nicotinic receptors via allosteric modulation; however, the effects appear to be highly dependent on the concentrations of agonist and galantamine. It is not yet clear whether these concentrations are related to those achieved in the brain of patients with Alzheimer's disease within therapeutic dose ranges. Preclinical studies have shown that donepezil and galantamine also significantly increase nicotinic receptor density, and increased receptor density may be associated with enhanced synaptic strengthening through long-term potentiation, which is related to cognitive function. Despite these differences in pharmacology, a review of clinical data, including head-to-head studies, has not demonstrated differences in efficacy, although they may have an impact on tolerability. It seems clear that whatever the subsidiary modes of action, clinical evidence supporting acetylcholinesterase inhibition as the mechanism by which cholinesterase inhibitors treat the symptoms of Alzheimer's disease is accumulating. Certainly, as a class, the currently approved cholinesterase inhibitors (donepezil, galantamine, rivastigmine and tacrine) provide important benefits in patients with Alzheimer's disease and these drugs offer a significant advance in the management of dementia.     

Novel tetrahydroacridine derivatives with iodobenzoic acid moiety as multifunctional acetylcholinesterase inhibitors

New synthesized series of 9‐amino‐1,2,3,4‐tetrahydroacridine derivatives with iodobenzoic acid moiety were studied for their inhibitory activity toward cholinesterase and against β‐amyloid aggregation. All novel molecules 3a–3i interacted with both cholinesterases—acetylcholinesterase and butyrylcholinesterase—delivered nanomolar IC₅₀ values. The structure–activity relationship showed that N‐butyl moiety derivatives are stronger inhibitors toward AChE and BuChE than N‐ethyl and N‐propyl moieties compounds. The most potent compound toward acetylcholinesterase was inhibitor 3f (IC₅₀ = 31.2 nm ), and it was more active than reference drug, tacrine (IC₅₀ = 100.2 nm ). Compound 3f showed strong inhibition of butyrylcholinesterase (IC₅₀ = 8.0 nm ), also higher than tacrine (IC₅₀ = 16.3 nm ). In the kinetic studies, compound 3f revealed mixed type of acetylcholinesterase inhibition. The computer modeling was carried out. The most active compound 3f was confirmed as peripheral anionic site inhibitor of acetylcholinesterase. Moreover, molecule 3f inhibited β‐amyloid aggregation (at the concentration 10 μm —24.96% of inhibition, 25 μm —72%, 50 μm —78.44%, and 100 μm —84.92%). Therefore, among all examined, compound 3f is the most promising molecule for further, more detailed research of novel multifunctional agents in the therapy of Alzheimer's disease.     

New classes of AChE inhibitors with additional pharmacological effects of interest for the treatment of Alzheimer's disease

Alzheimer's disease (AD) is associated to a gradual loss of attention and memory that have been associated to impairment of brain cholinergic neurotransmission, particularly a deficit of cholinergic neurons in the nucleus basalis of Meynert. Thus, it is not surprising that the first therapeutic target that has demonstrated therapeutic efficacy on cognition, behaviour and functional daily activities has been the inhibitors of acetylcholinesterase (AChE), i.e. tacrine, donepezil, rivastigmine and galanthamine. But not all inhibitors of AChE have the same potency to block the enzyme and have a different pharmacological profile. For instance, rivastigmine is a dual inhibitor of AChE and butyrylcholinesterase (BuChE), and galanthamine is a mild inhibitor of AChE and an allosteric potentiating ligand of neuronal nicotinic receptors for acetylcholine (nAChRs). In addition, we have recently found that galanthamine has neuroprotective effects by inducing calcium signals and the induction of the antiapoptotic protein Bcl-2. In this frame, we have been synthesizing new tacrine derivatives that keep their ability to inhibit AChE but that interfere with neuronal calcium overloading and prevent apoptosis. Some of these compounds exhibit neuroprotecting properties and thus, could be useful in the treatment of neurodegenerative and ischaemic brain diseases.     

Novel donepezil-based inhibitors of acetyl- and butyrylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation

A novel series of donepezil-tacrine hybrids designed to simultaneously interact with the active, peripheral and midgorge binding sites of acetylcholinesterase (AChE) have been synthesized and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), and AChE-induced A beta aggregation. These compounds consist of a unit of tacrine or 6-chlorotacrine, which occupies the same position as tacrine at the AChE active site, and the 5,6-dimethoxy-2-[(4-piperidinyl)methyl]-1-indanone moiety of donepezil (or the indane derivative thereof), whose position along the enzyme gorge and the peripheral site can be modulated by a suitable tether that connects tacrine and donepezil fragments. All of the new compounds are highly potent inhibitors of bovine and human AChE and BChE, exhibiting IC50 values in the subnanomolar or low nanomolar range in most cases. Moreover, six out of the eight hybrids of the series, particularly those bearing an indane moiety, exhibit a significant A beta antiaggregating activity, which makes them promising anti-Alzheimer drug candidates.     

Recent developments in the synthesis of acetylcholinesterase inhibitors

The acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities of a series of pyrano[2,3-b]quinolines (2, 3), [1,8]naphthyridines (5, 6), 4-amino-2,3-diaryl-5,6,7,8-tetrahydrofuro[2,3-b]quinolines (11-13)/ 4-amino-6,7,8,9-tetrahydro-2,3-diphenyl-5H-cyclohepta[e]furo[2,3-b]pyridine (14), 4-amino-5,6,7,8-tetrahydro-2,3-diphenylthieno[2,3-b]quinoline (15)/ 4-amino-6,7,8,9-tetrahydro-2,3-diphenyl-5H-cyclohepta[e]thieno[2,3-b]pyridine (16) are described. These compounds are tacrine analogues that have been prepared from readily available polyfunctionalized ethyl [6-amino-5-cyano-4H-pyran]-3-carboxylates (9, 10), ethyl [6-amino-5-cyanopyridine]-3-carboxylates (7, 8), 2-amino-3-cyano-4,5-diarylfurans (17-19) and 2-amino-3-cyano-4,5-diphenylthiophene (20) via Friedl?nder condensation with selected ketones. These compounds are competitive and, in a few cases, non-competitive inhibitors for AChE, the most potent being compound (14), though three-fold less active than tacrine. The BuChE inhibitory activity is only significant in compounds 11 and 14, ten-fold less active than tacrine. Furthermore, the products 12 and 13 are selective and moderate AChE inhibitors.     

Synthesis and biological evaluation of NO-donor-tacrine hybrids as hepatoprotective anti-Alzheimer drug candidates

In search of safer anti-Alzheimer drugs, 14 NO-donor-tacrine hybrids (1- 14) were synthesized and evaluated for their ability to inhibit cholinesterases and for vasorelaxation effects. Compounds 1- 13 showed good cholinesterases inhibitory activities in vitro, while 14, particularly, was highly selective, preferring butyrylcholinesterase rather than acetylcholinesterase. Four selected compounds (1, 9, 11, and 14) moderately relaxed the porcine pulmonary arteries in organ bath. In the hepatotoxicity study, significant hepatotoxicity was caused by tacrine but not by 9.     

Reversible and persistent decreases in cocaine self-administration after cholinesterase inhibition: different effects of donepezil and rivastigmine

We recently observed that pretreatment with the cholinesterase inhibitor, tacrine can produce long-lasting reductions in cocaine-reinforced behavior, described as persistent attenuation. In addition to inhibiting both acetylcholinesterase (AChE) and butyrylcholinesterase, tacrine can potentiate actions of dopamine. This study was carried out to evaluate the effects of donepezil (which selectively inhibits AChE) and rivastigmine (which inhibits both AChE and butyrylcholinesterase) on cocaine self-administration. High self-administration rats self-administered different doses of cocaine under a fixed ratio-5 schedule. Over a 4-day period, vehicle, donepezil, or rivastigmine was infused as animals were maintained in home cages (21 h per day), with signs of cholinergic stimulation (fasciculation, vacuous jaw movements, yawning, and diarrhea) scored by a blinded observer. Both compounds dose-dependently decreased cocaine self-administration, but differed in the potency and temporal pattern of their effects. Self-administration of low-dose cocaine was decreased to a greater degree by rivastigmine than donepezil (50% effective doses of 2.33 and 6.21 mg/kg/day, respectively), but this early effect did not continue beyond sessions immediately after treatment with rivastigmine. Group means for cocaine self-administration were decreased at some time points occurring between 1 and 3 days after the treatment with 10 mg/kg/day of donepezil (late effects), with decreases of more than 80% observed in some individual rats that persisted for 1 week or longer. Early, but not late, effects were correlated with signs of cholinergic stimulation. In summary, pretreatment with donepezil, but not rivastigmine produced persistent reductions in cocaine-reinforced behavior, which were not associated with signs of cholinergic stimulation.     

Ortho effects for inhibition mechanisms of butyrylcholinesterase by o-substituted phenyl N-butyl carbamates and comparison with acetylcholinesterase, cholesterol esterase, and lipase

Phenyl carbamates are used to treat Alzheimer's disease. These compounds inhibit acetylcholinesterase and butyrylcholinesterase. The goal of this work was to determine the chemical characteristics of ortho substituents that make some carbamates better inhibitors of butyrylcholinesterase than of acetylcholinesterase, cholesterol esterase, and lipase. The inhibition constants, Ki, Ki', kc, and ki were measured for nine different carbamates. The values were plotted according to Hammett, Taft-Kutter-Hansch, and Swan-Lupton to obtain constants that correlated the chemical nature of the substituents with inhibition potency. It was found that the negative charges of tetrahedral intermediates were more stabilized by ortho electron-withdrawing substituents of the inhibitors in butyrylcholinesterase than in acetylcholinesterase. This result confirmed formation of 3-pronged hydrogen bonds for the oxyanion hole of butyrylcholinesterase and 2-pronged hydrogen bonds for the oxyanion hole of acetylcholinesterase. Furthermore, it was found that ortho electron-donating substituents of the inhibitors accelerated inhibition of butyrylcholinesterase by ortho polar effects. Conformations of enzyme-inhibitor tetrahedral intermediates for butyrylcholinesterase were different from those for acetylcholinesterase and cholesterol esterase; ortho substituents in the tetrahedral intermediates were located far from the negatively charged carbonyl oxygens in butyrylcholinesterase, but close to the negatively charged carbonyl oxygens in acetylcholinesterase and cholesterol esterase. In conclusion, electron-donating substituents in the ortho position were better inhibitors of butyrylcholinesterase than acetylcholinesterase, while electron-withdrawing substituents were better inhibitors of acetylcholinesterase.     

Donepezil (E2020): a new acetylcholinesterase inhibitor. Review of its pharmacology, pharmacokinetics, and utility in the treatment of Alzheimer's disease

Donepezil is an acetylcholinesterase inhibitor under development for the treatment of mild-moderately Alzheimer's disease. In vitro, donepezil is about 10 times more potent than tacrine as an inhibitor of acetylcholinesterase. Donepezil is 500 - 1000 fold selective for acetylcholinesterase over butyrylcholinesterase. In animal models, donepezil produces positive effects on both working memory and long term memory. In man, donepezil is slowly absorbed from the gastrointestinal (GI) tract. The compound has a terminal elimination half-life of 50 - 70 h in young volunteers; in elderly volunteers, the half-life of the compound is extended to over 100 h. Donepezil is extensively metabolised after oral administration. The parent compound is 93% bound to plasma proteins. Results from two clinical trials with donepezil were published. The largest of these trials was a 12 week 161 patient Phase II investigation in the USA. Results from this investigation showed that donepezil produced dose-related improvements, with statistically significant effects occurring at doses of 3 and 5 mg/day. The results published to date suggest that donepezil will be a useful agent in the symptomatic treatment of Alzheimer's disease.