An Overview of Phenserine Tartrate, A Novel Acetylcholinesterase Inhibitor for the Treatment of Alzheimers Disease

Greig, Nigel H.; Sambamurti, Kumar; Yu, Qian; Brossi, Arnold; Bruinsma, Gosse; Lahiri, Debomoy K.

doi:10.2174/1567205054367829

Cited by 112 publications

(105 citation statements)

References 49 publications

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“…Physostigmine has served as a template in the development of several agents for AD, including a slow-release formulation of the parent compound (synapton, Forest Laboratories, St Louis, MO), its heptyl-carbamate (eptylstigmine, Mediolanum, Italy), both withdrawn from clinical development due to efficacy/toxicity issues, and the phenyl-carbamate, phenserine (National Institute on Aging, Baltimore, MD, and TorreyPines Therapeutics Inc., San Diego, CA) (Fig. 1C) in development for mild to moderately afflicted AD patients [29].…”

Section: Discussionmentioning

confidence: 99%

Kinetics of Human Serum Butyrylcholinesterase Inhibition by a Novel Experimental Alzheimer Therapeutic, Dihydrobenzodioxepine Cymserine

Kamal¹,

Klein²,

Luo

et al. 2007

Neurochem Res

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Cholinergic loss is the single most replicated neurotransmitter deficiency in Alzheimer's disease (AD) and has led to the use of acetylcholinesterase inhibitors (AChE-Is) and unselective cholinesterase inhibitors (ChE-Is) as the mainstay of treatment. AChE-Is and ChE-Is, however, induce dose-limiting adverse effects. Recent studies indicate that selective butyrylcholinesterase inhibitors (BuChE-Is) elevate acetylcholine (ACh) in brain, augment long-term potentiation, and improve cognitive performance in rodents without the classic adverse actions of AChE-Is and ChE-Is. BuChE-Is thereby represent a new strategy to ameliorate AD, particularly since AChE activity is depleted in AD brain, in line with ACh levels, whereas BuChE activity is elevated. Our studies have focused on the design and development of cymserine analogues to induce selective time-dependent brain BuChE inhibition, and on the application of innovative and quantitative enzyme kinetic analyses to aid selection of drug candidates. The quantitative interaction of the novel inhibitor, dihydrobenzodioxepine cymserine (DHBDC), with human BuChE was characterized. DHBDC demonstrated potent concentration-dependent binding with BuChE. The IC50 and specific new kinetic constants, such as KT50, PPC, KT1/2 and RI, were determined at dual substrate concentrations of 0.10 and 0.60 mM butyrylthiocholine and reaction times, and are likely attainable in humans. Other classical kinetic parameters such as Kia, Kma, Vma and Vmi were also determined. In synopsis, DHBDC proved to be a highly potent competitive inhibitor of human BuChE in comparison to its structural analogue, cymserine, and represents an interesting drug candidate for AD.

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Section: Discussionmentioning

confidence: 99%

Kinetics of Human Serum Butyrylcholinesterase Inhibition by a Novel Experimental Alzheimer Therapeutic, Dihydrobenzodioxepine Cymserine

Kamal¹,

Klein²,

Luo

et al. 2007

Neurochem Res

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“…Cholinesterase inhibitors were the first generation of such candidate therapeutics (11)(12)(13)(14)(15). A second generation of candidate therapeutics has included a series of attempts to inhibit the formation of amyloid plaques.…”

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confidence: 99%

Small molecule blockers of the Alzheimer Aβ calcium channel potently protect neurons from Aβ cytotoxicity

Díaz

Šimáková

Jacobson

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

107

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Alzheimer's disease (AD) is a common, chronic neurodegenerative disease that is thought to be caused by the neurotoxic effect of the Amyloid beta peptides (A␤). We have hypothesized that the intrinsic A␤ calcium channel activity of the oligomeric A␤ polymer may be responsible for the neurotoxic properties of A␤, and that A␤ channel blockers may be candidate AD therapeutics. As a consequence of a rational search paradigm based on the model structure of the A␤ channel, we have identified two compounds of interest: MRS2481 and an enatiomeric species, MRS2485. These are amphiphilic pyridinium salts that both potently block the A␤ channel and protect neurons from A␤ toxicity. Both block the A␤ channel with similar potency (Ϸ500 nM) and efficacy (100%). However, we find that inhibition by MRS2481 is easily reversible, whereas inhibition by MRS2485 is virtually irreversible. We suggest that both species deserve consideration as candidates for Alzheimer's disease drug discovery.brain ͉ neurodegeneration ͉ rational drug design ͉ drug ͉ toxicity A lzheimer's disease (AD) is a chronic neurodegenerative disease characterized behaviorally by progressive memory loss, and neuronal degeneration in the cerebral cortex, hippocampus, and elsewhere (1, 2). The neuropathology of AD is characterized by amyloid plaques and neuro-fibrillary tangles. The amyloid plaque material has been found to be composed principally of a 40Ϫ42-residue peptide, called amyloid ␤-peptide, or ''A␤'' (3). Both forms of A␤40/42 have been found to be kill neurons and certain other cells in culture. Altogether, these findings have provided strong support for the hypothesis that AD is due to neurotoxic effects of A␤ on susceptible neurons (4-10).The mechanism of A␤ neurotoxicity has been pursued for decades in hopes of translating such knowledge into a pharmaceutical therapy for AD. Cholinesterase inhibitors were the first generation of such candidate therapeutics (11-15). A second generation of candidate therapeutics has included a series of attempts to inhibit the formation of amyloid plaques. Active (16-23) and passive (24) immunization approaches are presently being tested. However, some patients in the active human immunization trials have developed meningoencephalitis (25,26). Yet another alternative has been to reduce the levels of A␤ in the brain by inhibiting the proteolytic enzymes associated with trimming APP into A␤ 40 or 42 (27-31).An entirely different approach to the mechanism of A␤ neurotoxicity has been developed following the observation that oligomers of A␤ peptides themselves formed calcium conducting channels in bilayer membranes in vitro (32)(33)(34)(35), and in intact neurons (36). The target of the A␤ peptide in biological and model membranes is phosphatidylserine (PS), the proapoptic signaling phospholipid (37). Subsequently the calcium channel properties of A␤ have been verified in many other laboratories (38-42). We and others have therefore hypothesized that calcium conducted into the target neurons by the A␤ channel might be respo...

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“…Our goal has been to investigate, design, and synthesize various classes of agents that can minimize cell dysfunction and death in neurodegenerative diseases (Greig et al, , 2005. The regulation of APP expression represents an important untapped approach to AD treatment because it is the originator of not only A␤ but also other APP-derived toxic fragments, and is a product of both neurons and glia that is up-regulated in AD by endogenous and environmental factors, such as cytokines and heavy metals (Lahiri et al, 2003b).…”

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confidence: 99%

“…(Ϫ)-Phenserine (phenserine) (Fig. 1), a physostigmine analog and AChE inhibitor that has reached clinical assessment, lowers APP and A␤ levels in cell culture and animal models (Greig et al, 2005). This latter action is not mediated by cholinergic stimulation of alternative APP-processing pathways but represents the inhibition of APP mRNA translation mediated by signals in its 5Ј-untranslated region (UTR) (Shaw et al, 2001).…”

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confidence: 99%

The Experimental Alzheimer's Disease Drug Posiphen [(+)-Phenserine] Lowers Amyloid-β Peptide Levels in Cell Culture and Mice

Lahiri¹,

Chen²,

Maloney³

et al. 2006

J Pharmacol Exp Ther

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133

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Major characteristics of Alzheimer's disease (AD) are synaptic loss, cholinergic dysfunction, and abnormal protein depositions in the brain. The amyloid ␤-peptide (A␤), a proteolytic fragment of amyloid ␤ precursor protein (APP), aggregates to form neuritic plaques and has a causative role in AD. A present focus of AD research is to develop safe A␤-lowering drugs. A selective acetylcholinesterase inhibitor, phenserine, in current human trials lowers both APP and A␤. Phenserine is dose-limited in animals by its cholinergic actions; its cholinergically inactive enantiomer, posiphen (ϩ)-[phenserine], was assessed. In cultured human neuroblastoma cells, posiphen, like phenserine, dose-and time-dependently lowered APP and A␤ levels by reducing the APP synthesis rate. This action translated to an in vivo system. Posiphen administration to mice (7.5-75 mg/kg daily, 21 consecutive days) significantly decreased levels of total APP (tissue mass-adjusted) in a dose-dependent manner. A␤ 40 and A␤ 42 levels were significantly lowered by posiphen (Ն15 mg/kg) compared with controls. The activities of ␣-, ␤-, and ␥-secretases were assessed in the same brain samples, and ␤-secretase activity was significantly reduced. Posiphen, like phenserine, can lower A␤ via multiple mechanisms and represents an interesting drug candidate for AD treatment.Alzheimer's disease (AD) is typified by progressive impairment in short-term memory and emotional disturbances that result from dysfunction and death of neurons in the hippocampus and associated regions of the limbic system and cerebral cortex. These aberrations are considered to result, in part, from microtubule-associated protein () tangles and abnormal aggregates of cytoskeletal proteins (Cairns et al., 2004), oxidative stress, and the overproduction and accumulation of amyloid-␤ peptide (A␤) in and surrounding neurons (Selkoe, 2005).This 39-to 43-amino acid peptide (molecular mass ϳ4.1 kDa) is a core constituent of amyloid plaques and results from two catalytic cleavages of the larger integral membrane protein, amyloid-␤ precursor protein (APP; ϳ110 -130 kDa), at the N terminus (␤-secretase) and C terminus (␥-secretase) of A␤ (Sambamurti et al., 2002;Lahiri et al., 2003b;Selkoe, 2005). Significant evidence indicates that A␤ changes conformation from a physiological to a pathological, fibrillar peptide form, which not only induces local structural disruption of synapses and neurite breakage but also results in cell death due to perturbed calcium homeostasis and oxidative stress. In addition, soluble aggregates of A␤ or A␤-derived diffusible ligands found in the brains of AD patients have been recently shown to target synapses (Gong et al., 2003) and play a role in inhibiting LTP (Walsh et al., 2002;LaFerla and Oddo, 2005). Conjointly, these studies point to the importance of A␤ in learning and memory, suggest a causative role of A␤ in AD pathophysiology, and thereby support its

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An Overview of Phenserine Tartrate, A Novel Acetylcholinesterase Inhibitor for the Treatment of Alzheimers Disease

Cited by 112 publications

References 49 publications

Kinetics of Human Serum Butyrylcholinesterase Inhibition by a Novel Experimental Alzheimer Therapeutic, Dihydrobenzodioxepine Cymserine

Kinetics of Human Serum Butyrylcholinesterase Inhibition by a Novel Experimental Alzheimer Therapeutic, Dihydrobenzodioxepine Cymserine

Small molecule blockers of the Alzheimer Aβ calcium channel potently protect neurons from Aβ cytotoxicity

The Experimental Alzheimer's Disease Drug Posiphen [(+)-Phenserine] Lowers Amyloid-β Peptide Levels in Cell Culture and Mice

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