Paper(s) concerning Aricept~Donepezil~E202053 reference(s) found.
Zhang N, Gordon ML Ref: Clin Interv Aging, 13:1963, 2018 : PubMed ESTHER: Zhang_2018_Clin.Interv.Aging_13_1963 PubMedSearch: Zhang 2018 Clin.Interv.Aging 13 1963 PubMedID: 30349215 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Abstract Donepezil, an acetylcholinesterase inhibitor (AChEI), has been widely used to treat Alzheimer's disease (AD) in China. However, there are few studies focusing on the efficacy and safety of donepezil in Chinese patients. In this review, we discuss 1) the efficacy of donepezil and its comparison with other AChEIs or memantine, 2) the therapeutic responses to donepezil and its influencing factors, and 3) the safety and tolerability of donepezil in Chinese patients with different stages of AD and amnestic mild cognitive impairment, and further compare the similarities and differences of the results between Chinese studies and previous Western studies that predominantly enrolled Caucasian subjects. We include Chinese clinical trials and other well-designed studies investigating donepezil or using donepezil as a positive control, in which the efficacy and/or safety of donepezil have been analyzed. Based on these studies, donepezil has been shown to be effective and safe in Chinese AD patients and may impact AD biomarkers, such as hippocampal atrophy, Abeta, and tau. In addition, the therapeutic response to donepezil may be influenced by apolipoprotein E or cytochrome P450 2D6 polymorphism. Title: Efficacy and Safety of Sustained Release Donepezil High Dose versus Immediate Release Donepezil Standard Dose in Japanese Patients with Severe Alzheimer's Disease: A Randomized, Double-Blind Trial Homma A, Atarashi H, Kubota N, Nakai K, Takase T Ref: J Alzheimers Dis, 52:345, 2016 : PubMed ESTHER: Homma_2016_J.Alzheimers.Dis_52_345 PubMedSearch: Homma 2016 J.Alzheimers.Dis 52 345 PubMedID: 26967222 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Abstract BACKGROUND: Donepezil is an established treatment for mild, moderate, and severe Alzheimer's disease (AD). An international study demonstrated superior efficacy of sustained release (SR) 23 mg/day donepezil over immediate release (IR) 10 mg/day donepezil for cognitive function, but not global function in moderate-to-severe AD. OBJECTIVE: To demonstrate the superiority of SR 23 mg/day donepezil over IR 10 mg/day donepezil in Japanese patients with severe AD (SAD). Title: Use of donepezil in elderly patients with Alzheimer's disease--a Hawaii based study Alagiakrishnan K, Wong W, Blanchette PL Ref: Hawaii Med J, 59:57, 2000 : PubMed ESTHER: Alagiakrishnan_2000_Hawaii.Med.J_59_57 PubMedSearch: Alagiakrishnan 2000 Hawaii.Med.J 59 57 PubMedID: 10800254 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Abstract Donepezil (Aricept) is a reversible acetylcholinesterase inhibitor which is indicated for the treatment of mild to moderate dementia of the Alzheimer's type. We did a retrospective analysis of 41 elderly Alzheimer's subjects of different ethnic groups including a large number of Asian and Hawaiian patients. Donepezil appears to be clinically effective in patients of different ethnicities with mild to moderate Alzheimer's disease, even at advanced age. Title: Huprine X is a Novel High-Affinity Inhibitor of Acetylcholinesterase That Is of Interest for Treatment of Alzheimer's Disease Camps P, Cusack B, Mallender WD, Achab RE, Morral J, Munoz-Torrero D, Rosenberry TL Ref: Molecular Pharmacology, 57:409, 2000 : PubMed ESTHER: Camps_2000_Mol.Pharmacol_57_409 PubMedSearch: Camps 2000 Mol.Pharmacol 57 409 PubMedID: 10648652 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020, HuprineX, Tacrine Abstract Inhibitors of the enzyme acetylcholinesterase (AChE) slow and sometimes reverse the cognitive decline experienced by individuals with Alzheimer's disease. Huperzine A, a natural product used in traditional Chinese herbal medicine, and tacrine (Cognex) are among the potent AChE inhibitors used in this treatment, but the search for more selective inhibitors continues. We report herein the synthesis and characterization of (-)-12-amino-3-chloro-9-ethyl-6,7, 10,11-tetrahydro-7,11-methanocycloocta[b]quinoline hydrochloride (huprine X), a hybrid that combines the carbobicyclic substructure of huperzine A with the 4-aminoquinoline substructure of tacrine. Huprine X inhibited human AChE with an inhibition constant K(I) of 26 pM, indicating that it binds to this enzyme with one of the highest affinities yet reported. Under equivalent assay conditions, this affinity was 180 times that of huperzine A, 1200 times that of tacrine, and 40 times that of E2020 (donepezil, Aricept), the most selective AChE inhibitor currently approved for therapeutic use. The association and dissociation rate constants for huprine X with AChE were determined, and the location of its binding site on the enzyme was probed in competition studies with the peripheral site inhibitor propidium and the acylation site inhibitor edrophonium. Huprine X showed no detectable affinity for the edrophonium-AChE complex. In contrast, huprine X did form a ternary complex with propidium and AChE, although its affinity for the free enzyme was found to be 17 times its affinity for the propidium-AChE complex. These data indicated that huprine X binds to the enzyme acylation site in the active site gorge but interferes slightly with the binding of peripheral site ligands. Title: The relationship between donepezil and behavioral disturbances in patients with Alzheimer's disease Cummings JL, Donohue JA, Brooks RL Ref: American Journal of Geriatry & Psychiatry, 8:134, 2000 : PubMed ESTHER: Cummings_2000_Am.J.Geriatr.Psychiatry_8_134 PubMedSearch: Cummings 2000 Am.J.Geriatr.Psychiatry 8 134 PubMedID: 10804074 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Abstract The authors tested the hypothesis that behavioral disturbances are reported at significantly lower rates by caregivers of Alzheimer's disease (AD) patients receiving the antidementia drug donepezil, compared with a group of patients receiving no antidementia drug treatment. Patients administered donepezilfor 6 months (n=84) were compared with patients not on donepezil (n=248). Patients taking donepezil had significantly lower levels of behavioral disturbances than patients not receiving this agent (P< or =0.011). Specifically, donepezil patients were described as significantly (P< or =0.05) less likely to be threatening, destroy property, and talk loudly. Also, significantly fewer patients receiving donepezil were treated with sedatives (P< or =0.005). These findings support the growing body of evidence that cholinesterase inhibitors have psychotropic properties and reduce behavioral disturbances in patients with AD. Title: Rivastigmine, a new-generation cholinesterase inhibitor for the treatment of Alzheimer's disease Jann MW Ref: Pharmacotherapy, 20:1, 2000 : PubMed ESTHER: Jann_2000_Pharmacotherapy_20_1 PubMedSearch: Jann 2000 Pharmacotherapy 20 1 PubMedID: 10641971 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Abstract Rivastigmine is a cholinesterase inhibitor (ChEI) with a structural formula different from that of currently available ChEIs. Tacrine and donepezil are classified as short-acting or reversible agents since binding to acetylcholinesterase enzyme (AChE) is hydrolyzed within minutes. Rivastigmine is classified as an intermediate-acting or pseudo-irreversible agent due to its long inhibition on AChE of up to 10 hours. Preclinical biochemical studies indicated that rivastigmine has central nervous system selectivity over peripheral inhibition. It ameliorated memory impairment in rats with forebrain lesions. The drug is rapidly absorbed orally, with a bioavailability of 0.355 and low protein binding (40%). Its elimination half-life is less than 2 hours, and it is converted to an inactive metabolite at the site of action, bypassing hepatic metabolic pathways. Its disposition essentially is unaltered in patients with renal or hepatic impairment. It also has dose-dependent effects on AChE inhibition. In the two large multicenter clinical trials (total 1324 patients) that used a forced-dosage titration scheme, rivastigmine 6-12 mg/day was superior to placebo on three cognitive and functioning scales (p<0.001). Gastrointestinal symptoms are the most frequently reported adverse events. They occurred mostly during the dosage titration phase and decreased during the maintenance phase. Rivastigmine offers clinicians another therapeutic agent to treat Alzheimer's disease. Title: Molecular modelling and QSAR of reversible acetylcholines-terase inhibitors Kaur J, Zhang MQ Ref: Curr Med Chem, 7:273, 2000 : PubMed ESTHER: Kaur_2000_Curr.Med.Chem_7_273 PubMedSearch: Kaur 2000 Curr.Med.Chem 7 273 PubMedID: 10637365 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Abstract Acetylcholinesterase (AChE) inhibitors are an important class of medicinal agents useful for the treatment of Alzheimer s disease, glaucoma, myasthenia gravis and for the recovery of neuromuscular block in surgery. To rationalize the structural requirements of AChE inhibitors we attempt to derive a coherent AChE-inhibitor recognition pattern based on literature data of molecular modelling and quantitative structure-activity relationship (QSAR) analyses. These data are summarised from nearly all therapeutically important chemical classes of reversible AChE inhibitors, e.g., derivatives of physostigmine, tacrine, donepezil and huperzine A. Interactions observed from X-ray crystallography between these inhibitors and AChE have also been incorporated and compared with modelling and QSAR results. It is concluded that hydrophobicity and the presence of an ionizable nitrogen are the pre-requisites for the inhibitors to interact with AChE. However the mode of interaction i.e., the 3-dimensional (3D) positioning of the inhibitor in the active site of the enzyme varies among different chemical classes. It is also recognised that water molecules play crucial roles in defining these different 3D positioning. The information on AChE-inhibitor interactions provided should be useful for future discovery of new chemical classes of AChE inhibitors, especially from De Novo design and hybrid construction. Title: Inhibitory effect of orally administered donepezil hydrochloride (E2020), a novel treatment for Alzheimer's disease, on cholinesterase activity in rats Kosasa T, Kuriya Y, Matsui K, Yamanishi Y Ref: European Journal of Pharmacology, 389:173, 2000 : PubMed ESTHER: Kosasa_2000_Eur.J.Pharmacol_389_173 PubMedSearch: Kosasa 2000 Eur.J.Pharmacol 389 173 PubMedID: 10688981 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Abstract Donepezil hydrochloride ((+/-)-2-[(1-benzylpiperidin-4-yl)methyl]-5, 6-dimethoxy-indan-1-one monohydrochloride: E2020: donepezil) is a potent and selective acetylcholinesterase inhibitor developed for the treatment of Alzheimer's disease. The present experiments were designed to compare the inhibitory effects of orally administered donepezil and other cholinesterase inhibitors, tacrine (9-amino-1,2, 3,4-tetrahydroacridine hydrochloride), (S)-N-ethyl-3-[(1-dimethyl-amino)ethyl]-N-methyl-phenylcarbamate hydrogentartrate (ENA-713, rivastigmine) and 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4, 5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone fumarate (TAK-147), on the cholinesterase activity in the brain and plasma of rats. Moreover, in order to validate the cholinesterase inhibition data, we measured the brain and plasma concentrations of these drugs. Oral administration of donepezil, tacrine, ENA-713 or TAK-147, caused a dose-dependent inhibition of brain and plasma cholinesterase activities. The ID(50) values of these compounds for brain cholinesterase activity were 6.3, 40.5, 7.2 and 26.8 micromol/kg, respectively. On the other hand, the ID(50)170, 9.7 and 51.2 micromol/kg, respectively. Thus, the ratios of the ID(50)4.2, 1.3 and 1.9, respectively. Brain and plasma concentrations of donepezil, tacrine and TAK-147 increased dose-dependently. The ratios of the concentrations (brain/plasma) of these compounds were 6.1-8.4 for donepezil, 14.5-54.6 for tacrine and 7.0-20.6 for TAK-147. The values of 50% inhibitory concentration of these drugs in the brain were 0.42, 3.5 and 1.1 nmol/g, respectively. In contrast, the brain and plasma concentrations of ENA-713 at all doses, except the two highest doses, were below the quantification limit. These results suggest that orally administered donepezil satisfactorily penetrates into the brain and inhibits cholinesterase there, and that donepezil is a potent and selective inhibitor of brain cholinesterase in comparison with plasma cholinesterase in vivo. Title: [Pharmacological properties of donepezil hydrochloride (Aricept), a drug for Alzheimer's disease] Ogura H, Kosasa T, Araki S, Yamanishi Y Ref: Nihon Yakurigaku Zasshi, 115:45, 2000 : PubMed ESTHER: Ogura_2000_Nihon.Yakurigaku.Zasshi_115_45 PubMedSearch: Ogura 2000 Nihon.Yakurigaku.Zasshi 115 45 PubMedID: 10876815 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Abstract One of the most consistent changes associated with Alzheimer's disease (AD) is a deficit in central cholinergic neurotransmission. Donepezil hydrochloride (DPZ), a novel class of cholinesterase (ChE) inhibitors, inhibits degradation of acetylcholine (ACh) and activates central cholinergic system. In in vitro studies, DPZ more selectively inhibited acetylcholinesterase (IC50: 6.7 nM) than butyrylcholinesterase (IC50: 7400 nM), while tacrine inhibited both acetylcholinesterase (IC50: 77 nM) and butyrylcholinesterase (IC50: 69 nM). After oral dosing, DPZ (ID50: 2.6 mg/kg) inhibited brain ChE dose-dependently without any remarkable effect on ChE in the heart and small intestine, whereas tacrine (ID50: 9.5 mg/kg) inhibited ChE equally in the brain and peripheral tissues. Brain microdialysis revealed that DPZ (2.5 mg/kg) enhanced extracellular ACh concentrations in the cerebral cortex and hippocampus in rats. In behavioral studies, DPZ counteracted both the deficit in passive avoidance induced by lesioning of the nucleus basalis magnocellularis (0.125-1.0 mg/kg) and the impairment in acquisition of a hidden-platform water maze task after lesioning of the medial septum in rats (0.5 mg/kg). DPZ also inhibited the scopolamine-induced impairment of radial maze performance (0.5 mg/kg). Placebo-controlled clinical studies of 12- and 24-week treatments of DPZ (5 mg, 10 mg/day) clearly showed an improvement in cognitive scores of probable AD patients. Title: Donepezil, a centrally acting acetylcholinesterase inhibitor, alleviates learning deficits in hypocholinergic models in rats Ogura H, Kosasa T, Kuriya Y, Yamanishi Y Ref: Methods Find Exp Clin Pharmacol, 22:89, 2000 : PubMed ESTHER: Ogura_2000_Methods.Find.Exp.Clin.Pharmacol_22_89 PubMedSearch: Ogura 2000 Methods.Find.Exp.Clin.Pharmacol 22 89 PubMedID: 10849891 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Abstract Donepezil is a member of a new class of centrally acting cholinesterase inhibitors which preferentially inhibit acetylcholinesterase rather than butyrylcholinesterase. The effects of donepezil on learning impairments were investigated in some hypocholinergic models in rats. In nucleus basalis magnocellularis (NBM)-lesioned rats, donepezil alleviated deficits in passive avoidance response at a dose of 0.125 mg/kg and higher, while tacrine had only a tendency toward improved performance. Donepezil at 0.5 mg/kg effectively counteracted acquisition impairments in the water maze task induced by lesions of the medial septum; tacrine had no significant effects on impairments in this task. Scopolamine caused an increase of errors in the 8-arm radial maze. Donepezil significantly decreased scopolamine-induced errors in the radial maze at 0.5 mg/kg, whereas tacrine decreased errors at 2 mg/kg. These results suggest that donepezil can clearly minimize learning impairments induced by treatments that cause central cholinergic deficiencies in rats. These findings support the clinical efficacy of donepezil in Alzheimer's disease. Title: Comparison of inhibitory activities of donepezil and other cholinesterase inhibitors on acetylcholinesterase and butyrylcholinesterase in vitro Ogura H, Kosasa T, Kuriya Y, Yamanishi Y Ref: Methods Find Exp Clin Pharmacol, 22:609, 2000 : PubMed ESTHER: Ogura_2000_Methods.Find.Exp.Clin.Pharmacol_22_609 PubMedSearch: Ogura 2000 Methods.Find.Exp.Clin.Pharmacol 22 609 PubMedID: 11256231 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Abstract This study was designed to compare the in vitro inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) of donepezil and some other cholinesterase (ChE) inhibitors which have been developed for the treatment of Alzheimer's disease. The carbamate derivatives physostigmine and rivastigmine needed preincubation to exhibit appropriate anti-ChE activity. The maximum ChE inhibition by physostigmine developed within 30-60 min, while the inhibitory effect of rivastigmine on AChE and BuChE activities reached its peak after 48 and 6 h, respectively. The order of inhibitory potency (IC50) towards AChE activity under optimal assay conditions for each ChE inhibitor was: physostigmine (0.67 nM) > rivastigmine (4.3 nM) > donepezil (6.7 nM) > TAK-147 (12 nM) > tacrine (77 nM) > ipidacrine (270 nM). The benzylpiperidine derivatives donepezil and TAK-147 showed high selectivity for AChE over BuChE. The carbamate derivatives showed moderate selectivity, while the 4-aminopyridine derivatives tacrine and ipidacrine showed no selectivity. The inhibitory potency of these ChE inhibitors towards AChE activity may illustrate their potential in vivo activity. Title: Donepezil Hydrochloride (E2020) and Other Acetylcholinesterase Inhibitors Sugimoto H, Iimura Y, Kawakami Y, Yamanishi Y Ref: Curr Med Chem, 7:303, 2000 : PubMed ESTHER: Sugimoto_2000_Curr.Med.Chem_7_303 PubMedSearch: Sugimoto 2000 Curr.Med.Chem 7 303 PubMedID: 10637367 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Abstract A wide range of evidence shows that acetylcholinesterase (AChE) inhibitors can interfere with the progression of Alzheimer's disease (AD). The successful development of these compounds was based on a well-accepted theory that the decline in cognitive and mental functions associated with AD is related to the loss of cortical cholinergic neurotransmission. The earliest known AChE inhibitors, namely, physostigmine and tacrine, showed modest improvement in the cognitive function of Alzheimer's patients. However, clinical studies show that physostigmine has poor oral activity, brain penetration and pharmacokinetic parameters while tacrine has hepatotoxic liability. Studies were then focused on finding a new type of acetylcholinesterase inhibitor that would overcome the disadvantages of these two compounds. Donepezil hydrochloride inaugurates a new class of AChE inhibitors with longer and more selective action with manageable adverse effects. Currently, there are about 19 new Alzheimer's drugs in various phases of clinical development. Title: Effects of donepezil on emotional/behavioral symptoms in Alzheimer's disease patients Weiner MF, Martin-Cook K, Foster BM, Saine K, Fontaine CS, Svetlik DA Ref: J Clin Psychiatry, 61:487, 2000 : PubMed ESTHER: Weiner_2000_J.Clin.Psychiatry_61_487 PubMedSearch: Weiner 2000 J.Clin.Psychiatry 61 487 PubMedID: 10937606 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Abstract BACKGROUND: This open-label study examined the effects of the reversible cholinesterase inhibitor donepezil on emotional/behavioral symptoms in Alzheimer's disease (AD) patients. METHOD: Patients were diagnosed as having probable/possible AD by National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS/ADRDA) criteria. This study used the CERAD Behavior Rating Scale for Dementia (CBRSD) and its subscales to evaluate a group of 25 AD patients treated with donepezil. Dosage was increased at 4 months for most patients from 5 to 10 mg q.h.s. Analysis of variance was used to compare scores over a period of 12 months. These patients were also compared, using t tests, to a reference group that had received no donepezil or other anticholinesterase. Title: Clinical profile of donepezil in the treatment of Alzheimer's disease Doody RS Ref: Gerontology, 45:23, 1999 : PubMed ESTHER: Doody_1999_Gerontology_45_23 PubMedSearch: Doody 1999 Gerontology 45 23 PubMedID: 9876215 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Abstract Although the underlying pathogenesis of Alzheimer's disease (AD) is not fully understood, one of its key features is the widespread loss of central cholinergic innervation, known to be fundamental for cognitive processes. This finding led to the hypothesis that pharmacological enhancement of acetylcholine (ACh) neurotransmission may alleviate the symptoms of AD. Currently, cholinergic therapy, particularly cholinesterase (ChE) inhibition, represents the most realistic approach to the symptomatic treatment of AD. Donepezil HCl, for example, is a piperidine-based, reversible acetylcholinesterase (AChE) inhibitor, chemically distinct from other ChE inhibitors and rationally designed for the symptomatic treatment of AD. It is highly selective for centrally acting AChE, with little or no affinity for butyrylcholinesterase, present predominantly in the periphery. Phase I and II clinical trials demonstrated donepezil's favourable pharmacokinetic, pharmacodynamic and safety profile with no requirement for dose modification in the elderly or in patients with renal or hepatic impairment. Furthermore, its long half-life supports a simple and convenient once-daily dosing regimen. Subsequent to encouraging phase II clinical trial results, two pivotal, randomized, double-blind phase III trials (of 15 and 30 weeks' duration) demonstrated highly significant improvements in cognition and global function in mild to moderately severe AD patients treated with either 5 or 10 mg/day donepezil compared with placebo. Adverse events in the phase II and III trials, primarily cholinergic in nature, were transient and generally mild in severity and resolved during continued donepezil administration. Thus, the donepezil clinical trials programme has shown that this drug is a clinically effective and well-tolerated, once-daily treatment for the symptoms of mild to moderately severe AD. Title: Structure of acetylcholinesterase complexed with E2020 (Aricept): implications for the design of new anti-Alzheimer drugs Kryger G, Silman I, Sussman JL Ref: Structure, 7:297, 1999 : PubMed ESTHER: Kryger_1999_Structure_7_297 PubMedSearch: Kryger 1999 Structure 7 297 PubMedID: 10368299 Gene_locus related to this paper: torca-ACHE Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Abstract BACKGROUND: Several cholinesterase inhibitors are either being utilized for symptomatic treatment of Alzheimer's disease or are in advanced clinical trials. E2020, marketed as Aricept, is a member of a large family of N-benzylpiperidine-based acetylcholinesterase (AChE) inhibitors developed, synthesized and evaluated by the Eisai Company in Japan. These inhibitors were designed on the basis of QSAR studies, prior to elucidation of the three-dimensional structure of Torpedo californica AChE (TcAChE). It significantly enhances performance in animal models of cholinergic hypofunction and has a high affinity for AChE, binding to both electric eel and mouse AChE in the nanomolar range. RESULTS: Our experimental structure of the E2020-TcAChE complex pinpoints specific interactions responsible for the high affinity and selectivity demonstrated previously. It shows that E2020 has a unique orientation along the active-site gorge, extending from the anionic subsite of the active site, at the bottom, to the peripheral anionic site, at the top, via aromatic stacking interactions with conserved aromatic acid residues. E2020 does not, however, interact directly with either the catalytic triad or the 'oxyanion hole', but only indirectly via solvent molecules. Title: [Treatment of Alzheimer's disease: acetylcholinesterase inhibitors]. Lopez-Pousa S, Lombardia Fernandez C Ref: Neurologia, 14:180, 1999 : PubMed ESTHER: Lopez-Pousa_1999_Neurologia_14_180 PubMedSearch: Lopez-Pousa 1999 Neurologia 14 180 PubMedID: 10363493 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Abstract AIM The cognitive deficiency of Alzheimer's disease is attributed to a dysfunction in the cerebral cholinergic systems. Current drug treatments are directed at stimulating cholinergic transmission. The aim of this study was to evaluate the latest cholinergic drugs available an those about to appear in the market. METHODS: A review of the most recent studies published regarding the physiopathology of Alzheimer disease and the results following treatment with donepezil, rivastigmine and metriphonate was carried out. RESULTS: Donepezil is a specific, reversible acetylcholinesterase inhibitor of close to 100% absorption and a half-life of 70 h, achieving stable concentrations at approximately 3 weeks. Patients treated with a single daily dosis of 5 or 10 mg improve in the ADAS-Cog scale. The medication is initiated with a dosis of 5 mg/day. Rivastigmine is a competitive, pseudoirreversible inhibitor with a half-life of 2 h, although it acts for approximately 10 h. The Adas-Cog scale and the CIBIC-Plus improve in patients treated with a daily dosis of 6 or 12 mg taken in two doses. Administration should be initiated at low doses (3 mg/day) which are progressively increased. Metriphonate is a prodrug of short life which inhibits acetylcholinesterase through a metabolite (DDVP) with a half-life in the circulation of 2 h. Improvement is observed in the ADAS-Cog scale and the CIBIC-Plus and in behavior disorders at doses of 0.3 and 0.65 mg/kg/day. Doses between 30 and 60 mg/day are effective. Title: Huperzine-A in capsules and tablets for treating patients with Alzheimer disease Xu SS, Cai ZY, Qu ZW, Yang RM, Cai YL, Wang GQ, Su XQ, Zhong XS, Cheng RY and Feng B <2 more author(s)> Xu SS, Cai ZY, Qu ZW, Yang RM, Cai YL, Wang GQ, Su XQ, Zhong XS, Cheng RY, Xu WA, Li JX, Feng B (- 2) Ref: Zhongguo Yao Li Xue Bao, 20:486, 1999 : PubMed ESTHER: Xu_1999_Zhongguo.Yao.Li.Xue.Bao_20_486 PubMedSearch: Xu 1999 Zhongguo.Yao.Li.Xue.Bao 20 486 PubMedID: 10678137 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Abstract AIM: To compare the efficacy and safety between huperzine-A (Hup) in capsules and tablets for treating patients with Alzheimer disease (AD). Title: Donepezil use in Alzheimer disease Barner EL, Gray SL Ref: Annals of Pharmacotherapy, 32:70, 1998 : PubMed ESTHER: Barner_1998_Ann.Pharmacother_32_70 PubMedSearch: Barner 1998 Ann.Pharmacother 32 70 PubMedID: 9475825 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Abstract OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug-drug interactions, and the therapeutic issues concerning the use of donepezil in patients with Alzheimer disease. DATA SOURCES: Published articles and abstracts in English were identified by MEDLINE (January 1985-July 1997) searches using the search terms donepezil, E2020, treatment of Alzheimer's disease, and cholinesterase inhibitors. Additional articles were identified from the bibliographies of the retrieved articles. Data were also obtained from approved product labeling. DATA EXTRACTION: The literature was assessed for adequate description of patients, methodology, and outcomes. DATA SYNTHESIS: Donepezil is a cholinesterase inhibitor that is selective and specific for acetylcholinesterase. It is metabolized by hepatic isoenzymes CYP2D6 and CYP3A4 and undergoes glucuronidation. Information about drug interactions is limited, but a potential for drug-drug interactions does exist, given the route of elimination. Donepezil has a relative bioavailability of 100% following oral administration and is not affected by the presence of food. In 15- and 30-week trials, donepezil was effective in patients with mild-to-moderate Alzheimer disease as shown by improvements on standard assessment instruments (i.e., the Alzheimer's Disease Assessment Scale-Cognitive Subscale, the Clinical Interview-Based Impression of Change with Caregiver Input). Adverse effects were comparable with those of placebo, and monitoring of liver function tests is not required. CONCLUSIONS: Donepezil is an effective symptomatic treatment for some patients with mild-to-moderate Alzheimer disease. Although no comparative trials have been reported, donepezil appears to be a safe alternative for tacrine, given its convenient once-daily dosing, minimal adverse effects, and lower total cost. Title: Comparative studies of huperzine A, E2020, and tacrine on behavior and cholinesterase activities Cheng DH, Tang XC Ref: Pharmacol Biochem Behav, 60:377, 1998 : PubMed ESTHER: Cheng_1998_Pharmacol.Biochem.Behav_60_377 PubMedSearch: Cheng 1998 Pharmacol.Biochem.Behav 60 377 PubMedID: 9632220 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020, HuperzineA, Tacrine Abstract Comparative effects of cholinesterase inhibitors (ChEI) huperzine A with E2020 and tacrine on the radial maze performance in ethylcholine mustard aziridinium ion (AF64A)-treated rat and inhibition of cholinesterase activity were studied. The intracerebroventricular (i.c.v.) injection of AF64A (3 nmol/side) caused significant impairment in the rat's ability to fulfill the partially baited maze paradigm. Oral huperzine A (0.5-0.8 mg/kg), E2020 (1.0-2.0 mg/kg), and tacrine (8.0 mg/kg) effectively reversed AF64A-induced working memory deficit. The doses that improved AF64A-induced memory deficit were correlated to about 25-30% (huperzine A) and less than 10% (E2020, tacrine) inhibition of acetylcholinesterase (AChE) activity in the cortex and hippocampus. Huperzine A, E2020 and tacrine all produced dose-dependent inhibition of brain AChE following i.c.v. and oral administration. Oral huperzine A exhibited higher efficacy on the inhibition of AChE in the cortex and hippocampus than those of E2020 and tacrine. Tacrine was more effective in inhibiting plasma butyrylcholinesterase (BCHE) than it was brain AChE. Conversely, the BCHE activity was less affected by huperzine A and E2020. The results showed that huperzine A had high bioavailability and more selective inhibition on AChE activity in cortex and hippocampus. Huperzine A fits more closely with the established criteria for an ideal AChE inhibitor to be used in clinical studies. Title: Drug and Therapeutics Bulletin defends its stance over donepezil [letter] Collier J Ref: British Medical Journal, 316:1092, 1998 : PubMed ESTHER: Collier_1998_Bmj_316_1092 PubMedSearch: Collier 1998 Bmj 316 1092 PubMedID: 9558999 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Title: Inhibition of cholinesterase-associated aryl acylamidase activity by anticholinesterase agents: focus on drugs potentially effective in Alzheimer's disease Costagli C, Galli A Ref: Biochemical Pharmacology, 55:1733, 1998 : PubMed ESTHER: Costagli_1998_Biochem.Pharmacol_55_1733 PubMedSearch: Costagli 1998 Biochem.Pharmacol 55 1733 PubMedID: 9634011 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020, BW284C51, Edrophonium, Heptylphysostigmine, HuperzineA, Neostigmine~Prostigmine, Physostigmine~Eserine, Tacrine Abstract The potency of a series of anticholinesterase (anti-ChE) agents and serotonin-related amines as inhibitors of the aryl acylamidase (AAA) activity associated with electric eel acetylcholinesterase (AChE) (EC 3.1.1.7) and horse serum butyrylcholinesterase (BCHE) (EC 3.1.1.8) was examined and compared with the potency of the same compounds as ChE inhibitors. Neostigmine, physostigmine, BW 284C51, (+/-)-huperzine A, E2020, tacrine, edrophonium and heptyl-physostigmine were, in that order, the most potent in inhibiting eel AChE-associated AAA activity, their inhibitor constant (Ki) values being in the range 0.02-0.37 microM. The rank order of the same compounds as AChE inhibitors basically paralleled that of AAA, although they were in general stronger on AChE (Ki = 0.001-0.05). The peripheral anionic site inhibitors propidium and gallamine were inactive on AChE-associated AAA. Serotonin and its derivatives were slightly stronger on AAA (Ki = 7.5-30 microM) than on AChE (Ki = 20-140 microM). Tacrine (IC50 = 0.03 microM), diisopropylfluorophosphate (IC50 = 0.04 microM), heptyl-physostigmine (IC50 = 0.11 microM), physostigmine (IC50 = 0.15 microM) and tetra-iso-propylpyrophosphoramide (iso-OMPA) (IC50 = 0.75 microM) were the most potent in inhibiting horse serum BCHE-associated AAA activity. Serotonin and related amines were very weak on BCHE-associated AAA activity. These results indicate that the inhibitory potencies of the active site anti-ChE agents on the AAA activity associated with eel AChE and horse serum BCHE are closely correlated with their action on the respective ChE. In addition, the efficacy of tacrine, E2020, heptyl-physostigmine and (+/-)-huperzine A in the treatment of Alzheimer's disease is unlikely to be related to the action of these drugs on ChE-associated AAA. Title: Invited review: Cholinesterase inhibitors for Alzheimer's disease therapy: from tacrine to future applications Giacobini E Ref: Neurochem Int, 32:413, 1998 : PubMed ESTHER: Giacobini_1998_Neurochem.Int_32_413 PubMedSearch: Giacobini 1998 Neurochem.Int 32 413 PubMedID: 9676739 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020, ENA-713~Rivastigmine, Galanthamine, Heptylphysostigmine, Physostigmine~Eserine, Tacrine, Trichlorfon~Metrifonate Abstract This review starts with an historical background of the pharmacological development of tacrine almost fifty years ago (1949). Tacrine is the first drug to be tested, clinically, on a large scale and to be registered (1993) for treatment of Alzheimer's disease. For the first time, clinical results of four second generation cholinesterase inhibitors (ChEI) (donepezil, ENA 713, eptastigmine and metrifonate) are reviewed and compared with other ChEI such as tacrine, physostigmine and galanthamine. Data based on more than 6000 patients show that second generation drugs are well tolerated and show evidence of clinical efficacy. Differences are mainly due to frequency of side effects, number of drop outs and percentage of improved patients. These results also demonstrate the presence of clinical efficacy for all ChEI tested so far. Clinical mechanism of action, levels of efficacy and differences among various ChEI are discussed. Future potential indications are suggested. The present data indicate that optimization of effects prolongation and maintenance of clinical gains will depend on further knowledge of the compounds pharmacodynamic properties. Title: How to cope with Alzheimer's disease? Hasegawa K Ref: Neurobiology of Aging, 19:S107, 1998 : PubMed ESTHER: Hasegawa_1998_Neurobiol.Aging_19_S107 PubMedSearch: Hasegawa 1998 Neurobiol.Aging 19 S107 PubMedID: 9562478 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Abstract Alzheimer's disease (AD) is the most common causative brain disease of primary dementia in the elderly. The incidence of AD rises exponentially with age. Many countries, where the aging population is a national problem, have to face how to cope with AD. The main strategies against AD include the estimation of the exact size of the problem, the elucidation of etiology of AD, the development of effective treatment, and the establishment of the caring system for AD sufferers in the community. A recent fruit of the research is the new cholinomimetic agent E2020 (Donepezil), which is a highly selective acetylcholinesterase inhibitor. As a result of clinical trials, statistically significant improvements were seen in cognitive function of AD patients. However, E2020 is one of the neurotransmitter substitution therapies and is not specifically linked to the etiological treatment. We have to make efforts to establish a definitive therapy for AD and this depends on basic research, such as the molecular biology of AD. Many AD patients and their families expect fruitful result from this symposium, which will be a big milestone for the research of AD toward the 21st Century. Title: Three-dimensional structure of a complex of E2020 with acetylcholinesterase from Torpedo californica Kryger G, Silman I, Sussman JL Ref: Journal de Physiologie Paris, 92:191, 1998 : PubMed ESTHER: Kryger_1998_J.Physiol.Paris_92_191 PubMedSearch: Kryger 1998 J.Physiol.Paris 92 191 PubMedID: 9789806 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Abstract The 3D structure of a complex of the anti-Alzheimer drug, E2020, also known as Aricept, with Torpedo californica acetylcholinesterase is reported. The X-ray structure, at 2.5 A resolution, shows that the elongated E2020 molecule spans the entire length of the active-site gorge of the enzyme. It thus interacts with both the 'anionic' subsite, at the bottom of the gorge, and with the peripheral anionic site, near its entrance, via aromatic stacking interactions with conserved aromatic residues. It does not interact directly with either the catalytic triad or with the 'oxyanion hole'. Although E2020 is a chiral molecule, and both the S and R enantiomers have similar affinity for the enzyme, only the R enantiomer is bound within the active-site gorge when the racemate is soaked into the crystal. The selectivity of E2020 for acetylcholinesterase, relative to butyrylcholinesterase, can be ascribed primarily to its interactions with Trp279 and Phe330, which are absent in the latter. Title: Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group Rogers SL, Doody RS, Mohs RC, Friedhoff LT Ref: Archives of Internal Medicine, 158:1021, 1998 : PubMed ESTHER: Rogers_1998_Arch.Intern.Med_158_1021 PubMedSearch: Rogers 1998 Arch.Intern.Med 158 1021 PubMedID: 9588436 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Abstract BACKGROUND: Donepezil hydrochloride (Aricept) is a selective acetylcholinesterase inhibitor developed for the treatment of Alzheimer disease. This phase 3 study was 1 of 2 pivotal trials undertaken to establish the efficacy and safety of using donepezil in patients with mild to moderately severe Alzheimer disease. OBJECTIVES: To further examine the efficacy and safety of using donepezil in the treatment of patients with mild to moderately severe Alzheimer disease. To examine the relationships between plasma donepezil concentrations, inhibition of red blood cell acetylcholinesterase activity, and clinical response. Title: A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease. Donepezil Study Group Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT Ref: Neurology, 50:136, 1998 : PubMed ESTHER: Rogers_1998_Neurology_50_136 PubMedSearch: Rogers 1998 Neurology 50 136 PubMedID: 9443470 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Abstract The efficacy and safety of donepezil as a treatment for patients with mild to moderate Alzheimer's disease (AD) was investigated in a multicenter, double-blind study. Patients were randomly assigned to treatment with placebo (n = 162), 5 mg/d donepezil (n = 154), or 10 mg/d donepezil (n = 157) for 24 weeks followed by a 6-week, single-blind placebo washout. The primary efficacy measures were the cognitive portion of the Alzheimer's Disease Assessment Scale (ADAS-cog) and the Clinician's Interview Based Assessment of Change-Plus (CIBIC plus), with the Mini-Mental State Examination (MMSE), Clinical Dementia Rating Scale-Sum of the Boxes (CDR-SB), and patient rated Quality of Life (QoL) used as secondary measures. Cognitive function, as measured by the ADAS-cog, was significantly improved in the 5- and 10-mg/d donepezil groups as compared with the placebo group at weeks 12, 18, and 24. Clinician's global ratings on the CIBIC plus also improved in both the 5- and 10-mg/d donepezil groups relative to placebo. At the end of the 6-week placebo washout phase, ADAS-cog scores and CIBIC plus ratings were not significantly different for the three groups. Significant treatment benefits were also observed consistently in both the 5- and 10-mg/d groups on the MMSE and the CDR-SB, but there was no consistent effect on the patient-rated QoL. Cholinergic side effects (primarily diarrhea, nausea, and vomiting) were reported more often in the 10-mg/d group than either the 5-mg/d or placebo groups. Side effects were transient and generally mild in severity. These data indicate that donepezil is a well-tolerated drug that improves cognition and global function in patients with mild to moderate AD. Title: Long-term efficacy and safety of donepezil in the treatment of Alzheimer's disease: an interim analysis of the results of a US multicentre open label extension study Rogers SL, Friedhoff LT Ref: European Neuropsychopharmacology, 8:67, 1998 : PubMed ESTHER: Rogers_1998_Eur.Neuropsychopharmacol_8_67 PubMedSearch: Rogers 1998 Eur.Neuropsychopharmacol 8 67 PubMedID: 9452942 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Abstract The long-term efficacy and safety of donepezil (up to 10 mg/day) was evaluated in a multicentre, non-randomised, open-label extension study of 133 patients with mild to moderate Alzheimer's disease (AD) who had completed a previous 14-week double-blind, placebo-controlled trial of donepezil. Assessments were conducted at three-weekly intervals for 12 weeks, then 12-weekly for up to 192 weeks. Efficacy, assessed by the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Clinical Dementia Rating-Sum of the Boxes (CDR-SB), was examined in comparison with published data of untreated AD patients. Safety was monitored by physical examinations, laboratory tests and vital sign measurements. Results of this interim analysis (at 98 weeks) show that donepezil produced improvements in cognition which remained superior to baseline for 38 weeks. CDR-SB likewise showed improvement, with scores maintained near baseline values for 26 weeks. Scores for both instruments then increased as expected in a progressive disease. However, the slope of score progression was less than has been historically reported for untreated patients. While the lack of a concurrent placebo group does not allow conclusions about the ability of donepezil to attenuate disease progression, the data, nonetheless, demonstrate that there is no loss of treatment benefit over 98 weeks. Donepezil was well tolerated, with no evidence of hepatotoxicity. Title: Aricept-induced nightmares in Alzheimer's disease: 2 case reports [letter] Ross JS, Shua-Haim JR Ref: J Am Geriatr Soc, 46:119, 1998 : PubMed ESTHER: Ross_1998_J.Am.Geriatr.Soc_46_119 PubMedSearch: Ross 1998 J.Am.Geriatr.Soc 46 119 PubMedID: 9434681 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Title: Tacrine and donepezil attenuate the neurotoxic effect of A beta(25-35) in rat PC12 cells Svensson AL, Nordberg A Ref: Neuroreport, 9:1519, 1998 : PubMed ESTHER: Svensson_1998_Neuroreport_9_1519 PubMedSearch: Svensson 1998 Neuroreport 9 1519 PubMedID: 9631459 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020, Tacrine Abstract The effect of the cholinesterase inhibitors tacrine and donepezil on A beta(25-35)-induced toxicity was investigated in rat pheochromocytoma PC12 cells by measuring the mitochondrial activity. Tacrine and donepezil was found in clinical relevant concentrations (10(-7)-10(-6) M) to attenuate A beta(25-35)-induced toxicity in PC12 cells. The neuroprotective effect of tacrine was blocked in the presence of the nicotinic antagonists mecamylamine (10(-5) M) and tubocurarine (10(-5) M), suggesting an interaction via nicotinic receptors. This study demonstrates that tacrine and donepezil can exert neuroprotective properties which might be of importance and contribute to the clinical efficacy of cholinesterase inhibitors in the treatment of Alzheimer's disease. Title: Donepezil medicated memory improvement in traumatic brain injury during post acute rehabilitation Taverni JP, Seliger G, Lichtman SW Ref: Brain Injury, 12:77, 1998 : PubMed ESTHER: Taverni_1998_Brain.Inj_12_77 PubMedSearch: Taverni 1998 Brain.Inj 12 77 PubMedID: 9483340 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Abstract Memory dysfunction is a recognized and difficult to treat complication of traumatic brain injury (TBI). Since medial-temporal lobe injury is a frequent contributor to memory dysfunction in TBI, it is likely that an acetylcholine deficit contributes to memory dysfunction in this population. Recently, Donepezil, an acetylcholine-esterase inhibitor which has demonstrated a high selectivity for neural Ach-esterase (with minimal side effects), was approved for use in dementia in Alzheimer's patients. Due to its promising results in Alzheimer's patients, and reports in the literature describing the use of physostigmine (an anti-cholinesterase with significant cardiovascular and autonomic side effects) to treat memory deficits in closed head injury, we decided to begin a trial of Donepezil in two patients with TBI who were experiencing long term static memory dysfunction refractory to conventional treatment. Both patients were admitted to our facility for physical and cognitive rehabilitation, and were started on a trial of Donepezil. Modified memory tests and subjective observations by both family and staff pointed to an improvement in memory within three weeks of starting Donepezil. Should these initial results be supported in larger trials, Donepezil may prove to be a valuable tool for the treatment of memory dysfunction in TBI. Title: Reversal of scopolamine-induced deficits in radial maze performance by (-)-huperzine A: comparison with E2020 and tacrine Wang T, Tang XC Ref: European Journal of Pharmacology, 349:137, 1998 : PubMed ESTHER: Wang_1998_Eur.J.Pharmacol_349_137 PubMedSearch: Wang 1998 Eur.J.Pharmacol 349 137 PubMedID: 9671090 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020, HuperzineA, Tacrine Abstract The effects of (-)-huperzine A ((5R,9R,11E)-5-amino-11-ethylidene-5,6,9,10-tetrahydro-7-methyl-5, 9-methanocycloocta[b]pyridin-2(1H)-one), and of the hydrochloride salt of E2020 ((R,S)-1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]-methyl piperidine) and tacrine (9-amino-1,2,3,4-tetrahydroacridine), on the scopolamine-induced memory deficits in rats were compared in a radial maze, using a 4-out-of-8 baiting procedure. Scopolamine (0.15 mg/kg, i.p.) caused significant impairment in the rats' ability to fulfil the radial maze task. (-)-Huperzine A (0.2-0.4 mg/kg, p.o.; 0.1-0.4 mg/kg, i.p.) had greater efficacy than E2020 (0.6-0.9 mg/kg, p.o.; 0.3-0.6 mg/kg, i.p.) and tacrine (1.5-2.5 mg/kg, p.o.; 0.3-0.6 mg/kg, i.p.) on the improvement of scopolamine-induced working and reference memory errors, respectively. There appeared to be an inverse bell-shape dose-dependent effect for all three compounds tested. The compared data demonstrate that (-)-huperzine A is the most potent and orally active acetylcholinesterase inhibitor of the three, and fits more closely the established criterions for an ideal acetylcholinesterase inhibitor to be used in clinical studies. Title: Absence of central cholinergic deficits in ApoE knockout mice Anderson R, Higgins GA Ref: Psychopharmacology (Berl), 132:135, 1997 : PubMed ESTHER: Anderson_1997_Psychopharmacology.(Berl)_132_135 PubMedSearch: Anderson 1997 Psychopharmacology.(Berl) 132 135 PubMedID: 9266610 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Abstract ApolipoproteinE (ApoE) genotype has recently been identified as a major risk factor for Alzheimer's disease (AD) but the mechanism(s) by which ApoE isoforms influence this disease remain unclear. Recent studies suggest that mice deficient in ApoE may exhibit impaired central cholinergic function. Since this neurotransmitter system has traditionally been associated with the pathogenesis of AD, we have further investigated the impact of ApoE gene deletion on this system. Female ApoE knockout (ko) mice, age 12 months, were compared with wild type littermate controls using a range of behavioural, biochemical and histochemical techniques. Pre-treatment with the cholinomimetic, donepezil (E2020; 2.5-5 mg kg-1 IP), produced significant hypothermia and induction of tremor in both wild type and ApoE ko mice. The magnitude of change did not significantly differ between the groups. Cognitive testing in the Morris water maze revealed that both wild type and ApoE ko mice could learn the location of a hidden escape platform with similar rates of acquisition and accuracy. Similarly, the behaviour of both genotypes proved indistinguishable in a Y-maze spontaneous alteration procedure. The protocols used for both cognitive tests were then shown to be sensitive to the disruptive effects of scopolamine (but not scopolamine methyl bromide). Following behavioural testing, choline acetyltransferase (ChAT) activity was measured in the hippocampus, frontal and entorhinal cortex and striatum. In each case there was no difference between the genotypes. In addition, coronal sections of striatum and anterior hippocampal regions of ApoE ko and wild type mice showed similar patterns of acetylcholinesterase (AChE) staining, with no qualitative or obvious quantitative difference. Finally, analysis of plasma cholesterol levels confirmed ApoE genotype. In conclusion, using a combination of behavioural, histochemical and biochemical measurements, we have failed to detect any significant differences in central cholinergic activity between wild type and ApoE ko mice. Title: Advertisements for donepezil. National policy needs to be set for prescribing of this drug Boothby H, Zaidi SM, Seth V, Khalaf S, Jameel H, Mahomed S, al Y Ref: BMJ, 315:1624, 1997 : PubMed ESTHER: Boothby_1997_BMJ_315_1624 PubMedSearch: Boothby 1997 BMJ 315 1624 PubMedID: 9437305 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Title: Donepezil Bryson HM, Benfield P Ref: Drugs & Aging, 10:234, 1997 : PubMed ESTHER: Bryson_1997_Drugs.Aging_10_234 PubMedSearch: Bryson 1997 Drugs.Aging 10 234 PubMedID: 9108896 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Abstract Donepezil is a specific and potent acetylcholinesterase inhibitor according to in vitro data. It displays primarily noncompetitive inhibitory activity. In vivo, donepezil inhibited acetylcholinesterase activity in human erythrocytes and increased extracellular acetylcholine levels in the cerebral cortex and hippocampus of the rat. Donepezil demonstrated efficacy in tests of reference memory in animals, but had less consistent activity in tests of working memory. Donepezil 5 or 10 mg/day was associated with significant improvements in cognitive function [assessed by the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog)] after 14 and 30 weeks and patient global function (Clinician's Interview-based Impression of Change incorporating caregiver input score) after 30 weeks, compared with placebo, in patients with mild to moderate Alzheimer's disease. After 2 years, donepezil 5 or 10 mg/day was associated with an ADAS-cog score approximately 4 points better than would be expected in untreated patients with mild to moderate Alzheimer's disease. The most common adverse events reported in association with donepezil 5 mg/day were gastrointestinal events (nausea/vomiting, diarrhoea, gastric upset and constipation) and dizziness. No hepatotoxicity was reported after 12 weeks' treatment. Title: Donepezil (Aricept) therapy for Alzheimer's disease Geldmacher DS Ref: Compr Ther, 23:492, 1997 : PubMed ESTHER: Geldmacher_1997_Compr.Ther_23_492 PubMedSearch: Geldmacher 1997 Compr.Ther 23 492 PubMedID: 9262925 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Title: Advertisements for donepezil (Aricept) in the BMJ. Advertisement suggests an unrealistic improvement in mental status Gray S Ref: BMJ, 314:1555, 1997 : PubMed ESTHER: Gray_1997_Bmj_314_1555 PubMedSearch: Gray 1997 Bmj 314 1555 PubMedID: 9183222 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Title: Advertisements for donepezil. Prices charged for private prescriptions for donepezil show huge variation Jones RW, Mann JB, Saunders SA Ref: BMJ, 315:1624, 1997 : PubMed ESTHER: Jones_1997_BMJ_315_1624 PubMedSearch: Jones 1997 BMJ 315 1624 PubMedID: 9437306 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Title: Effects of NIK-247 on cholinesterase and scopolamine-induced amnesia [published erratum appears in Methods Find Exp Clin Pharmacol 1997 Jun;19(5):364] Kojima J, Nakajima K, Ochiai M, Nakayama K Ref: Methods Find Exp Clin Pharmacol, 19:245, 1997 : PubMed ESTHER: Kojima_1997_Methods.Find.Exp.Clin.Pharmacol_19_245 PubMedSearch: Kojima 1997 Methods.Find.Exp.Clin.Pharmacol 19 245 PubMedID: 9228650 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020, NIK-247, Tacrine Abstract The effects of NIK-247 on cholinesterase, scopolamine-induced amnesia and spontaneous movement were examined and compared with those of the well-known cholinesterase inhibitors tacrine and E-2020. NIK-247, tacrine and E-2020 all strongly inhibited acetylcholinesterase (AChE) in human red blood cells (IC50s = 1.0 x 10(-6), 2.9 x 10(-7) and 3.7 x 10(-8) M, respectively). In addition, NIK-247 and tacrine, but not E-2020, strongly inhibited butyrylcholinestrase (BCHE) in human serum. All three drugs produced mixed inhibition of AChE activity. Moreover, the inhibitory effect of NIK-247 on AChE was reversible. All compounds at 0.1-1 mg/kg p.o. significantly improved the amnesia induced by scopolamine (0.5 mg/kg s.c.) in rats performing a passive avoidance task. The three compounds at 1 and 3 mg/kg p.o. did not significantly decrease spontaneous movement by rats. These findings suggest that NIK-247 at a low dose (0.1-1 mg/kg p.o.) improves scopolamine-induced amnesia but does not affect spontaneous movement. The findings suggest that NIK-247 may be a useful drug for the treatment of Alzheimer's disease. Title: Alzheimer's disease: an overview for the pharmacist McGuffey EC Ref: J Am Pharm Assoc, 3:347, 1997 : PubMed ESTHER: McGuffey_1997_J.Am.Pharm.Assoc_3_347 PubMedSearch: McGuffey 1997 J.Am.Pharm.Assoc 3 347 PubMedID: 9170813 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020, Tacrine Abstract Alzheimer's disease (AD) occurs more frequently in women, with an incidence greater than expected from longevity alone--a finding possibly related to reduced estrogen levels. The epidemiology, societal costs, clinical presentation, pathophysiology, etiology, and treatment of AD are reviewed. At present, only two drugs, tacrine and donepezil, are approved for treatment of AD. These drugs enhance central cholinergic activity by inhibiting cholinesterase. The goal of current drug development research is to halt progress of AD, and efforts are underway to discover ways to restore neuronal activity via neurotrophins and to prevent neuronal loss. Pharmacists are well positioned to assist AD patients (in the early stages) and caregivers by encouraging early intervention and by presenting realistic expectations about the disease and its treatment. A number of easily accessible resources for health care providers and consumers are presented. Title: Enhanced performance of spatial and visual recognition memory tasks by the selective acetylcholinesterase inhibitor E2020 in rhesus monkeys Rupniak NM, Tye SJ, Field MJ Ref: Psychopharmacology, 131:406, 1997 : PubMed ESTHER: Rupniak_1997_Psychopharmacology_131_406 PubMedSearch: Rupniak 1997 Psychopharmacology 131 406 PubMedID: 9226744 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020, Tacrine Abstract Hepatotoxicity limits the clinical utility of the cholinesterase inhibitor tacrine as a palliative therapy for Alzheimer's disease. The present studies examined the effects of E2020, a selective acetylcholinesterase inhibitor not associated with liver toxicity in man, on cognitive performance in rhesus monkeys using tasks employed previously to evaluate tacrine and other cholinomimetic agents. The ability of E2020 to prevent the induction of a cognitive impairment by the muscarinic receptor antagonist scopolamine was assessed using an automated spatial delayed response task. Coadministration of E2020 (0.5-1.75 mg/kg) caused a dose-dependent reversal of the scopolamine (0.03 mg/kg) induced impairment observed after retention intervals of 10 and 20 s. At the highest dose of E2020 examined (1.75 mg/kg), choice accuracy approached normal control levels. In this dose range, E2020 was well tolerated, but at the higher dose of 2 mg/kg, cholinergic side-effects were apparent. The effect of E2020 on choice accuracy in a visual recognition task was also assessed as this task does not require the use of scopolamine to disrupt performance and beneficial effects of cholinomimetics can therefore be detected at lower doses than in the spatial memory paradigm. In this task, administration of E2020 increased choice accuracy from 59 +/- 1% correct to up to 71 +/- 2% at doses of 0.03 and 0.05 mg/kg. No observable adverse effects were induced by E2020 in this dose range. The ability of E2020 to improve performance in these cognitive tasks resembles the profile of other cholinesterase inhibitors, including tacrine, that also improve cognitive function in Alzheimer's disease patients. Because of its more favourable clinical safety profile, E2020 may provide a significantly improved palliative therapy for dementia. Title: Functional activation of cerebral blood flow abolished by scopolamine is reversed by cognitive enhancers associated with cholinesterase inhibition: a positron emission tomography study in unanesthetized monkeys Tsukada H, Kakiuchi T, Ando I, Ouchi Y Ref: Journal of Pharmacology & Experimental Therapeutics, 281:1408, 1997 : PubMed ESTHER: Tsukada_1997_J.Pharmacol.Exp.Ther_281_1408 PubMedSearch: Tsukada 1997 J.Pharmacol.Exp.Ther 281 1408 PubMedID: 9190877 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020, Physostigmine~Eserine, Tacrine Abstract The effects of somatosensory stimulation on the regional cerebral blood flow (rCBF) response were studied in unanesthetized monkeys before and after treatment with scopolamine and three cognitive enhancers (physostigmine, E2020 and tacrine) that inhibit cholinesterase, using 15O-labeled water and high-resolution positron emission tomography. Under control conditions, somatosensory stimulation induced a significant increase in the rCBF response in the contralateral somatosensory cortex of monkey brain. Intravenous administration of scopolamine (50 microg/kg) resulted in abolishment of the rCBF response to stimulation. The rCBF response abolished by pretreatment with scopolamine was recovered by administration of physostigmine (1 or 10 microg/kg), E2020 (10 or 100 microg/kg) or tacrine (100 or 1000 microg/kg), in a dose-dependent manner. The effect of E2020 (100 microg/kg) on the rCBF response lasted for >4 hr, whereas the effects of physostigmine and tacrine were of shorter duration. These findings suggest that these compounds reversed the scopolamine-abolished rCBF response to somatosensory stimulation via enhancement of cholinergic neurotransmission, which was mainly induced by cholinesterase inhibition. Title: Advertisements for donepezil (Aricept) in the BMJ. Local committee has declined to approve NHS hospital prescription of donepezil Wagner N Ref: BMJ, 314:1555, 1997 : PubMed ESTHER: Wagner_1997_Bmj_314_1555 PubMedSearch: Wagner 1997 Bmj 314 1555 PubMedID: 9183223 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Title: Enhancing cognition in the intellectually intact Whitehouse PJ, Juengst E, Mehlman M, Murray TH Ref: Hastings Center Report, 27:14, 1997 : PubMed ESTHER: Whitehouse_1997_Hastings.Cent.Rep_27_14 PubMedSearch: Whitehouse 1997 Hastings.Cent.Rep 27 14 PubMedID: 9219019 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Abstract As science learns more about how the brain works, and fails to work, the possibility for developing "cognition enhancers" becomes more plausible. And the demand for drugs that can help us think faster, remember more, and focus more keenly has already been demonstrated by the market success of drugs like Ritalin, which tames the attention span, and Prozac, which ups the competitive edge. The new drug Aricept, which improves memory, most likely will join them. Whether such drugs are good for individuals, or for society, is an open question, one that demands far more public discussion. Title: Advertisements for donepezil. Review of drug in Drug and Therapeutics Bulletin is uninformed Wilkinson D Ref: BMJ, 315:1625, 1997 : PubMed ESTHER: Wilkinson_1997_BMJ_315_1625 PubMedSearch: Wilkinson 1997 BMJ 315 1625 PubMedID: 9437307 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Title: Huperzine A, a novel promising acetylcholinesterase inhibitor Cheng DH, Ren H, Tang XC Ref: Neuroreport, 8:97, 1996 : PubMed ESTHER: Cheng_1996_Neuroreport_8_97 PubMedSearch: Cheng 1996 Neuroreport 8 97 PubMedID: 9051760 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020, HuperzineA, Tacrine Abstract The effects of huperzine A on memory impairments induced by scopolamine were evaluated using a radial maze task and inhibition of cholinesterase in vitro compared with the effects of E2020 and tacrine. Scopolamine (0.2 mg kg-1) significantly impaired spatial memory in rats. Huperzine A (0.1-0.4 mg kg-1, p.o.), E2020 (0.5-1.0 mg kg-1, p.o.) and tacrine (1.0-2.0 mg kg-1, p.o.) could reverse these scopolamine-induced memory deficits. The ratios of huperzine A, E2020 and tacrine for butyrylcholinesterase:acetylcholinesterase determined by a colourimetric method were 884.57, 489.05, and 0.80, respectively. The results demonstrated that huperzine A was the most selective acetylcholinterase inhibitor, and improved the working memory deficit induced by scopolamine significantly better than did E2020 or tacrine, suggesting it may be a promising agent for clinical therapy of cognitive impairment in patients with Alzheimer's Disease. Title: The simulated binding of (+/-)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]m eth yl] -1H-inden-1-one hydrochloride (E2020) and related inhibitors to free and acylated acetylcholinesterases and corresponding structure-activity analyses Inoue A, Kawai T, Wakita M, Iimura Y, Sugimoto H, Kawakami Y Ref: Journal of Medicinal Chemistry, 39:4460, 1996 : PubMed ESTHER: Inoue_1996_J.Med.Chem_39_4460 PubMedSearch: Inoue 1996 J.Med.Chem 39 4460 PubMedID: 8893840 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Abstract The simulated binding profiles of acetylcholine, ACh, and the inhibitor (+/-)-2,3-dihydro-5,6- dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-on e hydrochloride (E2020), 1, and some of its analogs to acetylcholinesterase, AChE, were determined using full force field energetics and allowing complete conformational flexibility in both the ligand and receptor. A new mode of binding of ACh to AChE was found which involves the carboxyl oxygen of ACh interacting with Gly 118 and 119. Multiple modes of binding of 1 and some of its analogs were found which include alignment models observed in previous more restricted modeling studies. The key ligand-receptor interactions identified, and the corresponding energetics, are consistent on a relative basis, with observed binding constants for both the individual isomers of each of the inhibitors, as well as among the inhibitors themselves. The multiple modes of binding of 1 to AChE arises from small changes in binding at a single subsite and also from multiple subsite changes. Thus, an independent subsite model for ligand-receptor binding holds for some modes of binding, but not for others. A comparison of the simulated AChE-1 (and analog inhibitors) binding models to the receptor-independent 3D-QSARs previously developed for this class of inhibitors reveals extensive mutual consistency. The findings from these two modeling studies provides greater guidelines for inhibitor design than can be realized from either one. The combined docking and 3D-QSAR studies permit a detailed understanding of the SAR of more than 100 compound 1 analog inhibitors. A simple molecular recognition model can also be gleaned from the docking studies. A cylindrical "plug" (the inhibitor) having a large dipole moment must sterically fit into a cylindrical hole (the active site gorge of AChE), the lining of which also has a large dipole moment. Our simulations suggest that the dynamic "back door" to the active site of AChE does not form a large enough opening for sufficiently long time periods so as to be an effective entrance/exit pathway. Title: The efficacy and safety of donepezil in patients with Alzheimer's disease: results of a US Multicentre, Randomized, Double-Blind, Placebo- Controlled Trial. The Donepezil Study Group Rogers SL, Friedhoff LT Ref: Dementia, 7:293, 1996 : PubMed ESTHER: Rogers_1996_Dementia_7_293 PubMedSearch: Rogers 1996 Dementia 7 293 PubMedID: 8915035 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Abstract This study evaluated the efficacy and safety of donepezil in patients with mild to moderately severe Alzheimer's disease, and examined the relationships between plasma donepezil concentration, red blood cell acetylcholinesterase (AChE) activity and clinical response. The trial was of a multicenter, double-blind, parallel-group design and patients were randomised to once-daily treatment with either donepezil (1, 3 or 5 mg) or placebo. The 12-week double-blind phase was followed by a 2-week single-blind placebo washout. 161 patients (55-85 years of age) entered the study and 141 completed treatment. Patients treated with donepezil showed dose-related improvements in the Alzheimer's Disease Assessment Scale-cognitive subscale score (ADAS-cog) and in MMSF scores. The improvements in ADAS-cog were statistically significantly greater with donepezil 5 mg/day than with placebo. There was a 50% reduction in the percentage of patients showing clinical decline with donepezil at 5 mg/day (11%) relative to placebo (20%). In addition, a statistically significant correlation between plasma concentrations of donepezil and AChE inhibition was demonstrated. A plateau of inhibition (76-84%) was reached at plasma donepezil concentrations > 50 ng/ml. The correlation between plasma drug concentrations and ADAS-cog (p = 0.014), MMSE (p = 0.023) and patient quality of life scores, assessed by the patient (p = 0.037) were also statistically significant, as was the correlation between AChE inhibition and change in ADAS-cog (p = 0.008). The incidence of treatment-emergent adverse events with all three dosages of donepezil (64-68%) was comparable to that observed with placebo (65%). Donepezil had no clinically significant effect on vital signs, haematology or clinical biochemistry tests. Importantly, donepezil was not associated with any hepatotoxicity, as observed with acridine-based cholinesterase inhibitors. Title: Direct determination of E2020 enantiomers in plasma by liquid chromatography-mass spectrometry and column-switching techniques Matsui K, Oda Y, Ohe H, Tanaka S, Asakawa N Ref: Journal of Chromatography A, 694:209, 1995 : PubMed ESTHER: Matsui_1995_J.Chromatogr.A_694_209 PubMedSearch: Matsui 1995 J.Chromatogr.A 694 209 PubMedID: 7719466 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Abstract High-performance liquid chromatography with column switching and mass spectrometry (MS) was applied to the on-line determination and resolution of the enantiomers of E2020 (acetylcholinesterase inhibitor) in plasma. This system employs two avidin columns and fast atom bombardment (FAB)-MS. A plasma sample was injected directly into an avidin trapping column (10 mm x 4.0 mm I.D.). The plasma protein was washed out from the trapping column immediately while E2020 was retained. After the column-switching procedure, E2020 was separated enantioselectivity in an avidin analytical column. The separated E2020 enantiomers were specifically detected by FAB-MS without interference from metabolites of E2020 and plasma constituents. The limit of quantification for each enantiomer of E2020 in plasma was 1.0 ng/ml and the intra- and inter-assay relative standard deviations for the method were less than 5.2%. The assay was validated for enantioselective pharmacokinetic studies in the dog. Title: Kinetic study on the inhibition of acetylcholinesterase by 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine hydrochloride (E2020) Nochi S, Asakawa N, Sato T Ref: Biol Pharm Bull, 18:1145, 1995 : PubMed ESTHER: Nochi_1995_Biol.Pharm.Bull_18_1145 PubMedSearch: Nochi 1995 Biol.Pharm.Bull 18 1145 PubMedID: 8535413 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Abstract E2020 (1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine hydrochloride) is currently being developed as a treatment for senile dementia of the Alzheimer type. Its mechanism of action is to increase central cholinergic activity by inhibiting acetylcholinesterase (AChE) in the brain. In this study, the kinetics of the inhibitory action of E2020 on AChE was examined in comparison with its derivatives (2A1050 and 2A1034) and the reference compound tetrahydroaminoacridine (THA) all of which have a similar action. Analysis of the data using Lineweaver-Burk plots shows that inhibition by the test compounds fell into the category of mixed type. Inhibitor dissociation constants for the free enzyme (KI) and acetyl-enzyme (KI) of E2020 are one or two orders of magnitude lower than those of 2A1050, 2A1034 and THA. These findings indicate the strong inhibitory effect of E2020 on AChE. Title: Synthesis and structure-activity relationships of acetylcholinesterase inhibitors: 1-benzyl-4-[(5,6-dimethoxy-1-oxoindan-2- yl)methyl]piperidine hydrochloride and related compounds Sugimoto H, Iimura Y, Yamanishi Y, Yamatsu K Ref: Journal of Medicinal Chemistry, 38:4821, 1995 : PubMed ESTHER: Sugimoto_1995_J.Med.Chem_38_4821 PubMedSearch: Sugimoto 1995 J.Med.Chem 38 4821 PubMedID: 7490731 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Abstract Following the discovery of a new series of anti-acetylcholinesterase (anti-AChE) inhibitors such as 1-benzyl-4-[2-(N-benzoylamino)ethyl]piperidine (1), we reported that its rigid analogue, 1-benzyl-4-(2-isoindolin-2-ylethyl)piperidine (5), had more potent activity. We have extended the structure-activity relationship (SAR) study for the rigid analogue and found that the 2-isoindoline moiety in compound 5 can be replaced with a indanone moiety (8) without a major loss in potency. Among the indanone derivatives, 1-benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine (13e) (E2020) (IC50 = 5.7 nM) was found to be one of the most potent anti-AChE inhibitors. Compound 13e showed a selective affinity 1250 times greater for AChE than for butyrylcholinesterase. In vivo studies demonstrated that 13e has a longer duration of action than physostigmine at a dose of 5 mg/kg (po) and produced a marked and significant increase in acetylcholine content in rat cerebral cortex. We report the synthesis, SAR, and a proposed hypothetical binding site of 13e (E2020). Title: Acetylcholinesterase protection and the anti-diisopropylfluorophosphate efficacy of E2020 Galli A, Mori F, Benini L, Cacciarelli N Ref: European Journal of Pharmacology, 270:189, 1994 : PubMed ESTHER: Galli_1994_Eur.J.Pharmacol_270_189 PubMedSearch: Galli 1994 Eur.J.Pharmacol 270 189 PubMedID: 8039548 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Abstract The reversible noncovalent inhibitor of acetylcholinesterase (R,S)-1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]-methylpiperidine hydrochloride (E2020) was shown to inhibit electric eel acetylcholinesterase with high affinity in a mixed competitive-non-competitive way (Ki = 8.2 nM; Ki' = 13 nM). The pretreatment of electric eel acetylcholinesterase with E2020 dose-dependently prevented the inactivation of the enzyme by 40 microM diisopropylfluorophosphate. The EC50 for this protective effect (95% confidence limits) was 85 (76-96) nM, whereas under the same conditions E2020 IC50 was 12.3 (9.6-16) nM. E2020 injected together with atropine sulfate (17.4 mg/kg) into mice at doses in the range of 1.04-6.24 mg/kg 15 min before diisopropylfluorophosphate, caused a dose-dependent increase in diisopropylfluorophosphate LD50, resulting in protection ratios varying from 3.1 to 9.2. The effectiveness of E2020 antidotal effect was inversely correlated to the time between pretreatment and diisopropylfluorophosphate administration, being maximal when E2020 was injected 15 min, and possibly less than 15 min, before poisoning. From these experiments it is concluded that E2020 exerts a protective action against acute diisopropylfluorophosphate-poisoning in the mouse, presumably by protecting acetylcholinesterase from irreversible inactivation by this agent. Title: Prediction of the binding site of 1-benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]piperidine in acetylcholinesterase by docking studies with the SYSDOC program Pang YP, Kozikowski AP Ref: J Comput Aided Mol Des, 8:683, 1994 : PubMed ESTHER: Pang_1994_J.Comput.Aided.Mol.Des_8_683 PubMedSearch: Pang 1994 J.Comput.Aided.Mol.Des 8 683 PubMedID: 7738604 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020 Abstract In the preceding paper we reported on a docking study with the SYSDOC program for predicting the binding sites of huperzine A in acetylcholinesterase (AChE) [Pang, Y.-P. and Kozikowski, A.P., J. Comput.-Aided Mol. Design, 8 (1994) 669]. Here we present a prediction of the binding sites of 1-benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]piperidine (E2020) in AChE by the same method. E2020 is one of the most potent and selective reversible inhibitors of AChE, and this molecule has puzzled researchers, partly due to its flexible structure, in understanding how it binds to AChE. Based on the results of docking 1320 different conformers of E2020 into 69 different conformers of AChE and on the pharmacological data reported for E2020 and its analogs, we predict that both the R- and the S-isomer of E2020 span the whole binding cavity of AChE, with the ammonium group interacting mainly with Trp84, Phe330 and Asp72, the phenyl group interacting mainly with Trp84 and Phe330, and the indanone moiety interacting mainly with Tyr70 and Trp279. The topography of the calculated E2020 binding sites provides insights into understanding the high potency of E2020 in the inhibition of AChE and provides hints as to possible structural modifications for identifying improved AChE inhibitors as potential therapeutics for the palliative treatment of Alzheimer's disease. Title: The effects of novel cholinesterase inhibitors and selective muscarinic receptor agonists in tests of reference and working memory Dawson GR, Iversen SD Ref: Behavioural Brain Research, 57:143, 1993 : PubMed ESTHER: Dawson_1993_Behav.Brain.Res_57_143 PubMedSearch: Dawson 1993 Behav.Brain.Res 57 143 PubMedID: 8117420 Inhibitor(s) related to this paper: Aricept~Donepezil~E2020, Heptylphysostigmine Abstract In recent years muscarinic receptor agonists and cholinesterase inhibitors have been developed for the treatment of Alzheimer's disease. We have evaluated examples from both classes of compounds in rodent tests of reference and working memory, as well as tests that are sensitive to the side-effects of these compounds. Thus, three selective muscarinic receptor partial agonists L-689,660, (M1/M3), AF102B (M1/M3) and L-687,306 (M1) and two cholinesterase inhibitors, E2020 and eptastigmine, were compared in a mouse tail-flick (TF) test, a rat response sensitivity (RS) test, in rat tests of reference memory, passive avoidance (PA) or conditioned suppression of drinking (CSD), and working memory (delayed-matching-to-position, DMTP). In the TF test, all of the compounds tested, with the exception of L-687,306, (1.0-30.0 mg/kg) dose-dependently induced antinociception of which L-689,660 was the most potent (minimum effective dose (MED) = 0.03 mg/kg). In the RS test, all of the compounds, but again with the exception of L-687,306, (1.0-30.0 mg/kg), dose-dependently reduced response rates, of which L-689,660 was again the most potent (MED = 0.1 mg/kg). In the reference memory test, all the compounds reversed the effects of a scopolamine-induced deficit with L-687,306 being the most potent (MED = 0.01 mg/kg). By contrast, in the DMTP test, although both the cholinesterase inhibitors and L-687,306 reversed the effects of scopolamine-induced deficit, L-689,660 and AF102B were without effects. These results suggest that cholinesterase inhibitors and low efficacy M1 selective muscarinic receptor agonists can reverse the effects of a scopolamine-induced deficit in animal tests of reference and working memory at doses that do not induce the side-effects usually associated with cholinomimetics. | ||||||||
|
