cymserine and Alzheimer-Disease

Alzheimer's disease (AD), as the fourth leading cause of death among the elderly worldwide, has brought enormous challenge to the society. Due to its extremely complex pathogeneses, the development of multi-target directed ligands (MTDLs) becomes the major strategy for combating AD. Carbamate moiety, as an essential building block in the development of MTDLs, exhibits structural similarity to neurotransmitter acetylcholine (ACh) and has piqued extensive attention in discovering multifunctional cholinesterase inhibitors. To date, numerous preclinical studies demonstrate that carbamate-based cholinesterase inhibitors can prominently increase the level of ACh and improve cognition impairments and behavioral deficits, providing a privileged strategy for the treatment of AD. Based on the recent research focus on the novel cholinesterase inhibitors with multiple biofunctions, this review aims at summarizing and discussing the most recent studies excavating the potential carbamate-based MTDLs with cholinesterase inhibition efficacy, to accelerate the pace of pleiotropic cholinesterase inhibitors for coping AD.

Topics: Aged; Alzheimer Disease; Carbamates; Cholinesterase Inhibitors; Humans; Ligands

In this study, we designed, synthesized, and evaluated a series of carbamate derivatives of N-salicyloyl tryptamine as multifunctional therapeutic agents for the treatment of Alzheimer's disease (AD). After screening the acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) inhibitory activities, target compound 1g stood out as a mixed type reversible dual inhibitor of AChE and BChE. In addition, molecular docking studies were conducted to explore the actions on AChE and BChE. The results showed that 1g could decrease the level of pro-inflammatory cytokines NO, iNOS, IL-6, TNF-α, and ROS, increase the level of anti-inflammatory cytokines IL-4, and inhibit the aggregation of Aβ

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Binding Sites; Blood-Brain Barrier; Butyrylcholinesterase; Carbamates; Cholinesterase Inhibitors; Drug Design; Humans; Male; Maze Learning; Molecular Docking Simulation; Neuroprotective Agents; Protein Aggregates; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Tryptamines

Selective butyrylcholinesterase (BuChE)-inhibition, increases acetylcholine (ACh) levels. In rodents, this inhibition is known to boost cognition. Also, this occurs without the typical unwanted adverse effects of acetylcholinesterase-inhibitors or AChE-Is. The novel compound, fluorobenzylcymserine (FBC), is derived from our effort to design a selective BuChE-inhibitor. Also, we wanted to check whether butyrylcholinesterase-inhibitors (BuChE-Is) possessed an edge over AChE-Is in Alzheimer's disease (AD) in terms of efficacy and/or tolerance.. FBC was synthesized as reported earlier while enzymatic activity of BuChE was calculated by Ellman-technique. Molecular docking was performed using Autodock4.2. We applied classical as well as innovative analyses of enzyme-kinetics for exploring "FBC:human BuChE-interaction". The mode of inhibition and kinetic parameters were also determined.. Docking results displayed two strong interacting sites for FBC. One of these binding sites was previously identified as a deep narrow groove having polar aromatic residues while a second site was identified during this study which displayed better interaction and was lined with aliphatic and sulphur containing residues. At low concentrations of BuChE, the IC50 was found to be very low i.e. 4.79 and 6.10 nM for 12 and 36 µg, respectively, whereas it increased exponentially by increasing the units of BuChE.. These analyses indicate that FBC is an interesting AD drug candidate that could provide a potent and partial mixed type of inhibition of human BuChE.

Topics: Alzheimer Disease; Binding Sites; Butyrylcholinesterase; Cholinesterase Inhibitors; Humans; Inhibitory Concentration 50; Kinetics; Molecular Docking Simulation; Physostigmine

Synaptic loss, particularly related to the forebrain cholinergic system, is considered to be an early event that leads to Alzheimer's disease (AD) and has led to the development of acetylcholinesterase inhibitors (AChE-Is) as the mainstay of treatment for several degenerative disorders that culminate in dementia. The primary dose-limiting toxicities of all clinically available AChE-Is are, similar to useful actions on cognition, cholinergically mediated and they ultimately limit the value of this drug class in achieving anything but symptomatic improvements. In addition, AChE levels in brain areas associated with AD decline with disease progression, which likely ultimately limits the therapeutic utility of this drug class. New research indicates that selective inhibition of butyrylcholinesterase (BuChE), a closely related enzyme that is markedly elevated in AD brain, increases acetylcholine (ACh) and augments cognition in rodents free of the characteristic undesirable actions of AChE-Is. BuChE inhibition hence represents an innovative treatment approach for AD, and agents are currently being synthesized to optimally achieve this. The novel compound, tetrahydrofurobenzofuran cymserine (THFBFC), is derived from our effort to produce a potent and BuChE-selective inhibitor as a candidate to test the hypothesis that BuChE-Is would be efficacious and better tolerated than AChE-Is in AD. Herein, we applied innovative enzyme kinetic analyses to characterize the quantitative interaction of THFBFC with human BuChE. These provided values for the agent's IC(50), together with specific new kinetic constants, such as K (T50), K (T1/2), R (I), (o)K (RT), (o)P(max), K(PT) and PT(1/2), to aid define target concentrations for clinical translation. Additional classical kinetic parameters, including K(i), K(m)or K(s), k(cat) or V(max) and V (mi) were also determined. THFBFC proved to be a potent competitive inhibitor of human BuChE and, like its isomer dihydrobenzodioxepine cymserine, is a potentially interesting AD drug candidate.

Topics: Alzheimer Disease; Binding, Competitive; Butyrylcholinesterase; Drug Evaluation, Preclinical; Enzyme Inhibitors; Furans; Humans; Kinetics; Molecular Structure; Physostigmine; Serum

Accompanying the gradual rise in the average age of the population of most industrialized countries is a regrettable progressive rise in the number of individuals afflicted with age-related neurodegenerative disorders, epitomized by Alzheimer's disease (AD) but, additionally, including Parkinson's disease (PD) and stroke. The primary therapeutic strategy, to date, involves the use of cholinesterases inhibitors (ChEIs) to amplify residual cholinergic activity. The enzyme, acetylcholinesterase (AChE), along with other elements of the cholinergic system is depleted in the AD brain. In contrast, however, its sister enzyme, butyrylcholinesterase (BuChE), that likewise cleaves acetylcholine (ACh), is elevated and both AChE and BuChE co-localize in high amounts with the classical pathological hallmarks of AD. The mismatch between increased brain BuChE and depleted levels of both ACh and AChE, particularly late in the disease, has supported the design and development of new ChEIs with a preference for BuChE; exemplified by the novel agent, cymserine, whose binding kinetics are characterized for the first time. Specifically, as assessed by the Ellman method, cymserine demonstrated potent concentration-dependent binding with human BuChE. The IC50 was determined as 63 to 100 nM at the substrate concentration range of 25 to 800 microM BuSCh. In addition, the following new binding constants were investigated for human BuChE inhibition by cymserine: T(FPnubeta), K(nubeta), K(Bs), K(MIBA), M(IC50), D(Sc), R(f), (O)K(m), OIC100, K(sl), theta(max) and R(i). These new kinetic constants may open new avenues for the kinetic study of the inhibition of a broad array of other enzymes by a wide variety of inhibitors. In synopsis, cymserine proved to be a potent inhibitor of human BuChE in comparison to its structural analogue, phenserine.

Topics: Alzheimer Disease; Butyrylcholinesterase; Cholinesterase Inhibitors; Humans; Inhibitory Concentration 50; Kinetics; Physostigmine; Protein Binding