The Inhibitory Effect of Rivastigmine and Galantamine on Choline Transport in Brain Capillary Endothelial Cells

Lee, Na-Young; Kang, Young‐Sook

doi:10.4062/biomolther.2010.18.1.065

Cited by 22 publications

(12 citation statements)

References 23 publications

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“…Phenol 19 acts as a non-competitive inhibitor, accounting for a possible interaction of 19 with the PAS of the enzyme (Figure 5A). At the same time, the carbamate 20 showed a mixed-type inhibition, illustrated by a typical Lineweaver-Burk plot similar to those obtained with the covalent AChEI, rivastigmine (Figure 5B) [18].…”

Section: Resultssupporting

confidence: 61%

Inhibiting Acetylcholinesterase to Activate Pleiotropic Prodrugs with Therapeutic Interest in Alzheimer’s Disease

et al. 2019

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Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease which is still poorly understood. The drugs currently used against AD, mainly acetylcholinesterase inhibitors (AChEI), are considered clinically insufficient and are responsible for deleterious side effects. AChE is, however, currently receiving renewed interest through the discovery of a chaperone role played in the pathogenesis of AD. But AChE could also serve as an activating protein for pleiotropic prodrugs. Indeed, inhibiting central AChE with brain-penetrating designed carbamates which are able to covalently bind to the enzyme and to concomitantly liberate active metabolites in the brain could constitute a clinically more efficient approach which, additionally, is less likely to cause peripheral side effects. We aim in this article to pave the road of this new avenue with an in vitro and in vivo study of pleiotropic prodrugs targeting both the 5-HT4 receptor and AChE, in order to display a neuroprotective activity associated with a sustained restoration of the cholinergic neurotransmission and without the usual peripheral side effects associated with classic AChEI. This plural activity could bring to AD patients effective, relatively safe, symptomatic and disease-modifying therapeutic benefits.

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Section: Resultssupporting

confidence: 61%

Inhibiting Acetylcholinesterase to Activate Pleiotropic Prodrugs with Therapeutic Interest in Alzheimer’s Disease

et al. 2019

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“…GAL easily crosses the intestinal mucosa ( pPe GIT =5.060) which corresponds well to its oral bioavailability of 90% 52 . The value of 5.060 for pPe BBB, found in our previous study 39 , indicates for moderate ability to cross the BBB by passive diffusion but mediation by choline transport system has been suggested 55 . GAL binds mainly in CAS; only the methoxy group interacts with Phe295, Phe297 and Phe338 from PAS.…”

Section: Discussionmentioning

confidence: 77%

Novel hits for acetylcholinesterase inhibition derived by docking-based screening on ZINC database

Doytchinova

Atanasova

Valkova

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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The inhibition of the enzyme acetylcholinesterase (AChE) increases the levels of the neurotransmitter acetylcholine and symptomatically improves the affected cognitive function. In the present study, we searched for novel AChE inhibitors by docking-based virtual screening of the standard lead-like set of ZINC database containing more than 6 million small molecules using GOLD software. The top 10 best-scored hits were tested in vitro for AChE affinity, neurotoxicity, GIT and BBB permeability. The main pharmacokinetic parameters like volume of distribution, free fraction in plasma, total clearance, and half-life were predicted by previously derived models. Nine of the compounds bind to the enzyme with affinities from 0.517 to 0.735 µM, eight of them are non-toxic. All hits permeate GIT and BBB and bind extensively to plasma proteins. Most of them are low-clearance compounds. In total, seven of the 10 hits are promising for further lead optimisation. These are structures with ZINC IDs: 00220177, 44455618, 66142300, 71804814, 72065926, 96007907, and 97159977.

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“…It was also significantly inhibited by MPP + (Okura et al ., 2011) and ALC (Lee et al ., 2012). However, there was no effect by OCTs & OCTN1 substrate (TEA) (Tamai et al ., 2004; Ohtsuki and Terasaki, 2007; Chapy et al ., 2014) CTL1 substrate (choline) (Lee and Kang, 2010), OATP1-3, or MRP4 & 5 inhibitor (6-MP) (Mori et al ., 2004; Hosoya et al ., 2009; Lee et al ., 2011) (Table 3, 4).…”

Section: Discussionmentioning

confidence: 99%

Involvement of a Novel Organic Cation Transporter in Paeonol Transport Across the Blood-Brain Barrier

Gyawali

Krol

Kang

2019

Biomolecules & Therapeutics

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Paeonol has neuroprotective function, which could be useful for improving central nervous system disorder. The purpose of this study was to characterize the functional mechanism involved in brain transport of paeonol through blood-brain barrier (BBB). Brain transport of paeonol was characterized by internal carotid artery perfusion (ICAP), carotid artery single injection technique (brain uptake index, BUI) and intravenous (IV) injection technique in vivo . The transport mechanism of paeonol was examined using conditionally immortalized rat brain capillary endothelial cell line (TR-BBB) as an in vitro model of BBB. Brain volume of distribution (V D ) of [ 3 H]paeonol in rat brain was about 6-fold higher than that of [ 14 C]sucrose, the vascular space marker of BBB. The uptake of [ 3 H]paeonol was concentration-dependent. Brain volume of distribution of paeonol and BUI as in vivo and inhibition of analog as in vitro studies presented significant reduction effect in the presence of unlabeled lipophilic compounds such as paeonol, imperatorin, diphenhydramine, pyrilamine, tramadol and ALC during the uptake of [ 3 H]paeonol. In addition, the uptake significantly decreased and increased at the acidic and alkaline pH in both extracellular and intracellular study, respectively. In the presence of metabolic inhibitor, the uptake reduced significantly but not affected by sodium free or membrane potential disruption. Similarly, paeonol uptake was not affected on OCTN2 or rPMAT siRNA transfection BBB cells. Interestingly. Paeonol is actively transported from the blood to brain across the BBB by a carrier mediated transporter system.

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The Inhibitory Effect of Rivastigmine and Galantamine on Choline Transport in Brain Capillary Endothelial Cells

Cited by 22 publications

References 23 publications

Inhibiting Acetylcholinesterase to Activate Pleiotropic Prodrugs with Therapeutic Interest in Alzheimer’s Disease

Inhibiting Acetylcholinesterase to Activate Pleiotropic Prodrugs with Therapeutic Interest in Alzheimer’s Disease

Novel hits for acetylcholinesterase inhibition derived by docking-based screening on ZINC database

Involvement of a Novel Organic Cation Transporter in Paeonol Transport Across the Blood-Brain Barrier

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