Differential binding of phenothiazine urea derivatives to wild-type human cholinesterases and butyrylcholinesterase mutants

Darvesh, Sultan; Pottie, Ian R.; Darvesh, Katherine Valenta; McDonald, Robert; Walsh, Ryan; Conrad, Sarah; Penwell, Andrea; Mataija, Diane; Martin, Earl

doi:10.1016/j.bmc.2010.01.066

Cited by 36 publications

(29 citation statements)

References 41 publications

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“…Initial studies involved examination of the intermolecular reaction between urea derivative 3a 15 (Scheme 2), triflic anhydride, and furan, which is inexpensive, volatile, and highly activated in electrophilic aromatic substitution reactions (Scheme 2). 16 Exactly the same conditions were employed as noted for the reaction in Scheme 1, which employed 4-5 equivalents of triflic anhydride and 3 equivalents of DMAP at 0° C followed by warming to room temperature.…”

mentioning

confidence: 99%

Direct synthesis of arenecarboxamides through Friedel–Crafts acylation using ureas

Ying

Gamage

Lovro

et al. 2014

Tetrahedron Letters

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mentioning

confidence: 99%

Direct synthesis of arenecarboxamides through Friedel–Crafts acylation using ureas

Ying

Gamage

Lovro

et al. 2014

Tetrahedron Letters

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“…24 N -[2-( N ′, N ′-Diisopropylamino)ethyl]-10 H -phenothiazine-10-carboxamide ( 4 ) and anthracen-9-yl(10 H -phenothiazine-10-yl) methanone ( 5 ) were synthesized as described previously. 16,18 Purified human plasma wild-type BuChE and its mutants D70G, A328Y, F329A, and Y332A were a gift from Dr. Oksana Lockridge (University of Nebraska Medical Center, USA). BuChE concentration was calculated using the assumption of 62.5 unit/nmol (0.94 Δ A 412 /[min × nM]).…”

Section: Methodsmentioning

confidence: 99%

“…Studies with a series of N -10-carbonyl derivatives of phenothiazine 15−18 as well as N -10-alkyl phenothiazines such as ethopropazine 19 also indicate the relevance of aryl residues close to the mouth of the active site gorge of BuChE that are contiguous with the catalytic triad glutamate through the E-helix. 17 This helix (E325-Y332) includes tyrosine and phenylalanine residues (F329, Y332 in BuChE) whose side chains project into the active site gorge.…”

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confidence: 99%

Probing the Peripheral Site of Human Butyrylcholinesterase

et al. 2012

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Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) catalyze the hydrolysis of the neurotransmitter acetylcholine and, thereby, function as coregulators of cholinergic neurotransmission. For both enzymes, hydrolysis takes place near the bottom of a 20 Å deep active site gorge. A number of amino acid residues within the gorge have been identified as important in facilitating efficient catalysis and inhibitor binding. Of particular interest is the catalytic triad, consisting of serine, histidine, and glutamate residues, that mediates hydrolysis. Another site influencing the catalytic process is located above the catalytic triad toward the periphery of the active site gorge. This peripheral site (P-site) contains a number of aromatic amino acid residues as well as an aspartate residue that is able to interact with cationic substrates and guide them down the gorge to the catalytic triad. In human AChE, certain aryl residues in the vicinity of the anionic aspartate residue (D74), such as W286, have been implicated in ligand binding and have therefore been considered part of the P-site of the enzyme. The present study was undertaken to explore the P-site of human BuChE and determine whether, like AChE, aromatic side chains near the peripheral aspartate (D70) of this enzyme contribute to ligand binding. Results obtained, utilizing inhibitor competition studies and BuChE mutant species, indicate the participation of aryl residues (F329 and Y332) in the E-helix component of the BuChE active site gorge, along with the anionic aspartate residue (D70), in binding ligands to the P-site of the enzyme.

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“…But in AD brains, the activity of AChE decreases while that of BuChE gradually rises [16e18]. Therefore, BuChE appears as an increasingly important therapeutic target to improve cholinergic neurotransmission, as discussed in the literature in a number of publications [19,20], including phenothiazine derivatives [21,22].…”

Section: Introductionmentioning

confidence: 99%

N-Acylaminophenothiazines: Neuroprotective agents displaying multifunctional activities for a potential treatment of Alzheimer’s disease

González-Muñoz

Arce

López

et al. 2011

European Journal of Medicinal Chemistry

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Differential binding of phenothiazine urea derivatives to wild-type human cholinesterases and butyrylcholinesterase mutants

Cited by 36 publications

References 41 publications

Direct synthesis of arenecarboxamides through Friedel–Crafts acylation using ureas

Direct synthesis of arenecarboxamides through Friedel–Crafts acylation using ureas

Probing the Peripheral Site of Human Butyrylcholinesterase

N-Acylaminophenothiazines: Neuroprotective agents displaying multifunctional activities for a potential treatment of Alzheimer’s disease

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