Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.1.8 (cholinesterase)
12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of intercellular pathways in the ADH-dependent water transport was studied on the frog urinary bladder by means of acetylcholine (AC) and other cholinergic compounds. AC (10(-3) M) was found to cause a strong suppression of the pituitrin-stimulated water flow. Analogous effect was produced by AC on the osmotic flow stimulated by cyclic adenosine monophosphate (cAMP) and theolin. The antipituitrin effect was not reproduced either by nicotine, nor by potent M-cholinomimetic agents (methylfurmetide and F-2268), and was not prevented by M- and N-cholynolytic drugs (atropine, metacin, flaxedil, hexamethonium). However, the antipituitrin effect of AC was completely removed by the anticholinesterase drugs with different mode of action (eserine, proserine, armin, acridine iodmethylate, GD-42) in concentrations of 10(-6)--10(-3) M. It was concluded that the smooth muscles contraction with the subsequent closure of the intercellular spaces was not responsible for the antipituitrinic action of AC. This effect appears to be connected with cholinesterase activation. A possible role of the phosphoinositides in the water permeability regulation of the urinary bladder wall is discussed.
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PMID:[Effect of acetylcholine on the pituitrin induced osmotic flow of water through the wall of the frog urinary bladder]. 8 Oct 76

Simple method of continual monitoring of the rat blood cholinesterase activity in vivo was used to demonstrate its inhibition following i. m. administration of acridine and carbamate inhibitors. Another type of inhibition was demonstrated for different routes of administration of highly toxic organophosphate, VX. Reactivation of the blood cholinesterase was also monitored following intoxication with VX and soman and treated with obidoxime and atropine. This continual determination of cholinesterase activity represents an useful approach to study effects of cholinesterase inhibitors.
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PMID:An evaluation of continual determination of blood cholinesterase activity for inhibition studies. 130 Jun 33

This paper examines inhibition of acetylcholinesterase (AchE) and butyrylcholinesterase (BuchE) by tetrahydroaminoacridine (THA), an acridine analog under consideration for palliative treatment of Alzheimer's dementia. THA causes linear mixed inhibition of AchE hydrolysis of acetylthiocholine, a cationic substrate (KI = 3.8 x 10(-9) M), and linear competitive inhibition of AchE hydrolysis of 7-acetoxy-4-methylcoumarin, an uncharged substrate (KI = 6.8 x 10(-9) M), and N-methyl-7-dimethylcarbamoxyquinolinium, a cationic carbamate (KI = 1.5 x 10(-8) M). Propidium association with AchE in the presence of saturating concentrations of THA is characterized by a dissociation constant of 7.7 +/- 0.7 x 10(-6) M, a value within 2-fold of the dissociation constant in the absence of THA. Association of THA with AchE is, therefore, not mutually exclusive with association of propidium at the peripheral anionic site. Moreover, THA causes dissociation of decidium complexes with AchE at concentrations compatible with a dissociation constant of 7.0 +/- 0.4 x 10(-9) M. Similar relationships were observed for THA inhibition of BuchE hydrolysis of butyrylthiocholine (KI = 2.5 x 10(-8) M) and dissociation of decidium complexes with BuchE (KD = 1.9 +/- 0.1 x 10(-8) M). These kinetic and equilibrium data uniformly indicate that THA associates with AchE and BuchE with high affinity and that the subsequent inhibition comes about through ligand association at the active center rather than at a peripheral site. The noncompetitive component of inhibition reflects association of THA with the acyl-enzyme intermediate, with subsequent effects on the rate of deacylation.
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PMID:Interaction of tetrahydroaminoacridine with acetylcholinesterase and butyrylcholinesterase. 153 17

It was found that acetylcholine (ACh) at the concentration of 10(-3) M inhibited ADH-stimulated water transport through the wall of amphibian urinary bladder. This effect was suggested to be caused by an interaction of ACh with acetylcholinesterase (AChE) rather than by a stimulation of the M- or N-cholinoreceptor. The inhibitory action of ACh was completely suppressed in the presence of various AChE inhibitors (physostigmine, proserine, armine, Gd-42, acridine-iodmethylate), while an inhibitor of butyrylcholinesterase (BuChE), AD-4, failed to affect it. In accord with this observation the activity of AChE (but not of BuChE) was demonstrated in the urinary bladder epithelium. Since, in addition to the hydrosmotic effects of pituitrine, 8-arginine-vasopressin or oxytocin, ACh blocked also effects of forskolin or cyclic AMP, one may conclude that it acts at some post-cyclic AMP production stage. AChE-dependent inhibition of the ADH-stimulated water transport decreased significantly when the serosal pH was raising from 7.2 to 8.0, but was augmented by serosal acidification (pH 6.8), whereas such pH alterations did not affect the activity of the epithelium AChE. The effect of ACh under consideration was suppressed by adding amiloride (10(-4) M) to the serosal solution. Similarly, the ACh effect was blocked by an inhibitor of Ca-dependent K+ channels, 4-aminopyrdine, which in addition prevented the inhibition of the ADH-stimulated water transport by the serosal acidification. It was noteworthy that some other K+ channel blockers (Ba2+, Cs+, tetraethylammonium, apamine, quinine) did not affect either the water transport or the antipituitrine effect of ACh. In conclusion, we suggest that the inhibitory action of ACh on the ADH-stimulated water transport in the urinary bladder is mediated through the intracellular acidification resulting from ACh interaction with AChE. It is unlikely that the acidification is merely a consequence of the ACh hydrolysis, rather the ACh-AChE interaction induces directly an increase in the proton conductivity of the basolateral membrane of the urinary bladder epithelium.
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PMID:[Acetylcholinesterase and the ADH-dependent transport of water in the amphibian bladder]. 181 71

Rate control in acetylcholinesterase (AChE) involves a single anionic site whose anionic center controls rate-related biochemical and conformational changes in the E (free enzyme) and EA (acylated enzyme) conformers. Change in conformer structure and biochemistry affect binding, acylation, and hydrolysis. It is significant that the anionic-esteratic intersite distance is not altered during conformer change as E is converted to EA. In this enzyme system, cationic acetylcholine and anionic AChE are true structural, functional, and biochemical counterparts. The anionic center in the E conformer lies at the bottom of a sterically restricted, hydrophobic cleft < 8 A wide at the top and > 3 A wide at the bottom, while the anionic center in the EA conformer is relatively open. It is characterized by a decrease in the relative binding of hydrophobic cations and by an ability to bind large organic cations. Binding of acetylcholine, H+, or organic cations at the anionic site controls k2(acylation) in the E conformer and k3(hydrolysis) in the EA conformer. Acetylcholine binding forms the ES complex in which the cation maximizes k2. In the EAS complex, the cation reduces k3 and provides allosteric control. Anionic site structure and biochemistry and the effect of pH on k2 and k3 differentiates AChE from butyrylcholinesterase. This comprehensive study of kinetic and thermodynamic processes in AChE was made possible by the synthesis and/or use of families of over 30 cationic and acylation probes of known stereochemistry. They act as rulers of the E and EA conformers of AChE and provide comparative data on kinetic-based and thermodynamic-based constants. Cationic inhibitors affect decarbamylation rates in AChE and provide an additional set of comparative data related to the mechanism of substrate hydrolysis by AChE. Acridine araphanes are unique neural receptor and cholinergic enzyme probes. Their parallel plane and coplanar conformations are related to bridge length. Two parallel plane acridine araphanes are pure uncompetitive inhibitors of AChE. Scatchard plots of the binding of methylacridinium and 9-aminoacridine with the E conformer and 9-aminoacridine with the EA conformer indicate binding at a single anionic site. No ternary complex (EII or EAII) from two-site binding was detected. In AChE, nonspecific, low-level binding at surface ionic and hydrophobic areas is ubiquitous. Binding affinity differences greater than two orders of magnitude distinguish binding at the anionic site from low level binding at surface moieties. Surface binding provides environmental and stability changes in the enzyme but does not modify the fundamental biochemistry of the E and EA conformers.
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PMID:Conformers of acetylcholinesterase: a mechanism of allosteric control. 830 83

According to the cholinergic theory of Alzheimer's disease, the cognitive failure depends on a deficit in acetylcholine. The study reported above examines the efficacy and tolerability of cholinesterase inhibitors, such as tetrahydroamino acridine (THA), for the management of this pathology.
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PMID:[Use of cholinesterase inhibitors in Alzheimer disease]. 830 79

Acridine ligand affinity chromatography is an effective means of acetylcholinesterase (AChE) purification. However, the synthesis of these resins is laborious and expensive. We have developed an acridine ligand affinity resin that is easy to produce, inexpensive, and selective for AChE over butyrylcholinesterase. The resin is produced in a single synthetic step by attaching the aminoacridine tacrine to epoxy-activated Sepharose. AChE from bovine serum (59% yield), Torpedo electric organ (27-60% yield), and two commercial sources of eel AChE (> 92% yield) is purified using the affinity resin. One commercial source of eel AChE contains two proteins with molecular weights of 80 and 55 kDa upon purification, while two proteins with molecular weights of 55 and 25 kDa are isolated from the other commercial source, presumably representing degraded AChE. The degradation state of the commercially available eel AChE preparations did not influence their specific activities. The isolation of AChE from bovine serum results in a single 80-kDa protein. However, butyrylcholinesterase is not purified from the serum. Using the tacrine affinity resin, and 80-kDa AChE, solubilized from Torpedo electric organ membranes by protease digestion, can also be purified. Velocity sedimentation analysis of the Torpedo AChE reveals that the molecular forms isolated are either tetrameric or asymmetric when solubilized by collagenase or trypsin, respectively. Overall, the tacrine affinity resin which is simple and inexpensive to produce allows for the selective isolation of AChE from diverse biological matrices.
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PMID:Purification of acetylcholinesterase by tacrine affinity chromatography. 852 21

The potential of heptylphysostigmine tartrate (pyrrolo [2,3b] indol-5-ol, 3,3a,8,8a-hexahydro-1,3a,8-trimethylheptylcarbamate [ester, (3aS-cis)]) (MF201), a new second-generation cholinesterase inhibitor, to antagonize scopolamine-induced amnesia in rats was assessed in an 8-arm radial maze. Upon completing the training session, the rats were orally administered increasing doses of MF201 (2, 3, 4, 6 and 8 mg/kg) 60 min prior to a s.c. injection of scopolamine (0.25 mg/kg). 9-Amino-1,2,3,4-tetrahydroamino-acridine hydrochloride hydrate (tacrine) (0.25, 0.37, 0.5, 1 and 2 mg/kg), 1-benzil-4-[(5,6-dimethoxy-1-indanon)-2-yl]-methyl piperidine (E2020) (0.125, 0.18, 0.25 and 0.5 mg/kg) and physostigmine (0.15, 0.25, 0.5 and 1 mg/kg) were orally administered and rats were tested in the same task. As previously described, scopolamine induced an impairment in radial maze performance, measured in terms of total number of errors, total time taken to complete the task and the percentage of amnesic animals. The reversal of scopolamine-induced impairment was characterized by the presence of an inverted U-shaped dose-response curve. A significant antagonistic effect was achieved with a dose (mg/kg) of 0.25 for E2020, 0.5 for tacrine and physostigmine and 3, 4 and 6 for MF201, the latter manifesting a broader spectrum of activity (3-6 mg/kg). While the maximal active doses restored the scopolamine-induced modified pattern of arm entry, they were ineffective in reducing hypermotility, suggesting the drugs have a specific effect on cognitive function.
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PMID:An inverted U-shaped curve for heptylphysostigmine on radial maze performance in rats: comparison with other cholinesterase inhibitors. 879 Sep 86

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.
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PMID: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. 891 35

Acridines are nucleic acid intercalating compounds with properties relating to the complexity of their structure. Tetrahydroaminoacridine (tacrine, Cognex), a simple acridine, is a reversible inhibitor of cholinesterase activity available for the symptomatic treatment of Alzheimer's disease. Tacrine therapy causes sporadic elevations of aminotransferases in humans, and tacrine alters protein synthesis and ribosomal structure under short-term in vitro exposures in isolated hepatocytes from humans and other species. There is no clear relationship between transaminase elevation and liver damage in humans, and prolonged drug exposure to animals does not result in hepatic insult. Subcellular alterations have been described in isolated human and rodent hepatocytes, including degranulation and vesiculation of the endoplasmic reticulum (ER), aggregation of electron-dense structures within the ER, altered nuclei and nucleoli and detrimental structural and functional effects to mitochondria. Whether these changes in hepatocyte morphology and function are unique to tacrine or not is unknown, as human hepatocytes exposed to more complex acridines have not been characterized. In this study, we extended the results of in vitro studies with tacrine to acridine orange, 9-aminoacridine, quinacrine and proflavin. In primary human hepatocytes, these compounds caused a similar reduction of mitochondrial membrane potential with parallel ultrastructural changes. The 1-hydroxy and 7-hydroxy tacrine metabolites, acridine hydrochloride and acridine 9-carboxylic acid, and the non-acridine cholinesterase inhibitor eserine, did not induce characteristic subcellular ER changes but damaged mitochondria structure, reduced mitochondrial membrane potential and were cytotoxic. These data indicate that the tacrine-like subcellular changes in hepatocytes are reproducible with other acridines and cause mitochondrial dysfunction in human hepatocytes.
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PMID:Acridine-induced subcellular and functional changes in isolated human hepatocytes in vitro. 998 75


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