Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.7 (acetylcholinesterase)
 28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We describe prolonged apnea following electrotherapy in a patient who was also being treated with a topical organophosphate anticholinesterase, ecothiophate iodide (phospholine iodide), for glaucoma. The increased duration of action of succinylcholine resulted from low levels of serum cholinesterase that had been caused by the organophosphate. Attention is called to other drugs that directly or indirectly (by lowering serum cholinesterase) interact with succinylcholine chloride resulting in prolonged apnea. Other potential hazards of succinylcholine administration, such as hyperkalemia and cardiac arrhythmias, are also discussed.
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PMID:Hazards of succinylcholine administration during electrotherapy. 68 74

A new series of cyclic organophosphorus esters, 2-S-[2'-N,N-dialkylamino)ethyl]thio-1,3,2-dioxaphosphorinane 2-oxide and their quaternary derivatives, was synthesized and studied as potential antiglaucoma agents. Thes compounds inhibit acetylcholinesterase (E.C.3.1.1.7)at a bimoecular rate constant (ki) in the range of 10(3)-10(4) M-1 min-1. Values of the affinity (K) and phosphorylation (k') rate constants for this enzyme indicate that k' is responsible for the relatively low values of ki as compared with similar data for the open-chain analogues, O,O-diethyl phosphorothiolates (10(6) M-1 min-1). The mammalian toxicity of the new compounds in terms of acute LD50 values in mice is 1-3 x 10(3) less than that of phospholine, an open-chain analogue. In an initial clinical trial, one member of the new series (alkyl = C2H5) caused a significant decrease of intraocular pressure in aphakic glaucoma, while phospholine proved to be ineffective.
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PMID:Synthesis and properties of 2-S-(N,N-dialkylamino)ethyl)thio-1,3,2-dioxaphosphorinane 2-oxide and of the corresponding quaternary derivatives as potential nontoxic antiglaucoma agents. 95 Jun 51

In the present review an update on the medical therapy of open-angle glaucoma is given. Antiglaucomatous drugs that are rarely or no longer indicated are briefly discussed, as are the current medical therapy and perspectives of the medical management of glaucoma. In light of the pharmacological profiles of current antiglaucomatous agents, irreversible cholinesterase inhibitors, are out of date, and higher concentrations of clonidine eye drops and aqueous preparations of epinephrine-hydrocloride are also old-fashioned. The spectrum of current antiglaucomatous drugs is outlined and perspectives are indicated that will enrich our antiglaucomatous drug armamentarium in the near future. In this respect the development of pro-drugs and, new designs in the pharmaceutical preparation of traditional drugs are emphasized. In the field of new agents special emphasis is placed on topically applicable carbonic anhydrase inhibitors, the selective alpha-2-agonist apraclonidine and IOP-lowering prostaglandin derivatives. A series of agents is presented that are still experimental.
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PMID:[Drug therapy of glaucoma]. 208 99

Physostigmine (Phy) is one of the oldest drug isolated from Calabar beans and successfully used for the treatment of glaucoma in 1864. Since then, it has been widely employed for various therapeutic purposes. Recently, it has gained prominence because of its clinical trials in the treatment of Alzheimer's disease. Phy is also considered to be a potent prophylactic antidote for organophosphate poisoning. It is a reversible cholinesterase (ChE) inhibitor and has a short duration of action. It crosses the blood-brain barrier readily. Hence, it is a centrally acting carbamate. For the last 50 years, numerous authors have shown that pretreatment with Phy would rapidly improve the incapacitating effects of organophosphate intoxication in various animal species. Phy carbamylates to a portion of ChE enzyme and thus protects the enzyme from binding with organophosphate, which are irreversible ChE inhibitors. Organophosphates are metabolized very quickly in the body or bind to non-specific binding sites. The carbamylated ChE enzyme decarbamylates to free the enzyme for normal functioning. The rates of decarbamylation of butyrylcholinesterase (BuChE) in plasma and ChE in brain and muscle are different and are related to the half-life of Phy in these tissues. In addition to ChE inhibition, Phy has got a direct action on acetylcholine (ACh) receptor ionophore complex by interacting with the ACh-gated cation channels. Physostigmine has a half-life of 16, 23 and 30 min in rat, dog and man, respectively. The bioavailability of Phy is very low (about 2%) and it is extensively metabolized in the liver. Less than 4% of Phy is excreted unchanged in the urine and a portion is also eliminated in the bile. Physostigmine has a narrow margin of safety, and a slight increase in dose causes cholinergic symptoms, which can be counteracted by cholinolytic therapy. This review article deals with various aspects of physostigmine such as historical, therapeutic uses, mechanisms of action, methods for the determination, disposition and pharmacokinetics, toxicity and finally as an antidote against organophosphate intoxication.
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PMID:Physostigmine--an overview as pretreatment drug for organophosphate intoxication. 267 71

A 69 year old man receiving echothiophate eye drops for glaucoma was given a controlled infusion of succinylcholine during elective surgery for incisional hernia. Neuromuscular blockade was assessed by the measurement of the force of contraction of the adductor pollicis muscle. Only 9.5 mg succinylcholine were required for tracheal intubation and 1.1 mg/min for maintenance. When the infusion was stopped, recovery of neuromuscular transmission was rapid and uneventful. Plasma cholinesterase activity was 62 per cent below normal, but the enzyme was qualitatively normal. Thus, muscle relaxation can be achieved safely with a succinylcholine infusion in patients with decreased plasma cholinesterase activity if neuromuscular function is closely monitored.
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PMID:Controlled succinylcholine infusion in a patient receiving echothiophate eye drops. 728 94

The major compound responsible for toxicity to Artemia salina of some Fusarium tricinctum strains has been isolated, and its structure has been elucidated by spectroscopical methods, i.e. UV, IR, MS, 1H-NMR and 13C-NMR. The novel compound, trivially named visoltricin, is the first imidazole derivative produced by Fusarium spp., and its structure has been established as the methyl ester of 3-[1-methyl-4-(3-methyl-2-butenyl)-imidazol-5yl]-2-propenoic acid (molecular formula C13H18N2O2; MW = 234.297). Visoltricin was toxic to A. salina larvae (LD50 = 8.5 x 10(-7) M), and inhibited the growth of six human tumour cell lines (out of 60 lines tested) at concentrations lower than 10(-5) M. Tested on rabbit eye it showed an interesting miotic activity similar to that of pilocarpine, a miotic agent largely used in the therapy of glaucoma. This biological activity could be explained in part by the anticholinesterase properties shown by visoltricin towards both human serum and pure enzymes (EC 3.1.1.7 and EC 3.1.1.8). Kinetics studies showed for visoltricin a mixed-type and reversible inhibition of the EC 3.1.1.7 enzyme with the competitive inhibition constant (Ki) = 1.9 x 10(-4) M.
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PMID:Visoltricin, a novel biologically active compound produced by Fusarium tricinctum. 766 51

Cholinesterases form a family of serine esterases that arise in animals from at least two distinct genes. Multiple forms of these enzymes can be precisely localized and regulated by alternative mRNA splicing and by co- or posttranslational modifications. The high catalytic efficiency of the cholinesterases is quelled by certain very selective reversible and irreversible inhibitors. Owing largely to the important role of acetylcholine hydrolysis in neurotransmission, cholinesterase and its inhibitors have been studied extensively in vivo. In parallel, there has emerged an equally impressive enzyme chemistry literature. Cholinesterase inhibitors are used widely as pesticides; in this regard the compounds are beneficial with concomitant health risks. Poisoning by such compounds can result in an acute but usually manageable medical crisis and may damage the CNS and the PNS, as well as cardiac and skeletal muscle tissue. Some inhibitors have been useful for the treatment of glaucoma and myasthenia gravis, and others are in clinical trials as therapy for Alzheimer's dementia. Concurrently, the most potent inhibitors have been developed as highly toxic chemical warfare agents. We review treatments and sequelae of exposure to selected anticholinesterases, especially organophosphorus compounds and carbamates, as they relate to recent progress in enzyme chemistry.
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PMID:Anticholinesterases: medical applications of neurochemical principles. 772 78

A novel series of prostaglandin F2 alpha (PGF2 alpha) prodrugs, with acyl ester groups at the 9, 11, and 15 positions, was prepared in order to design clinically acceptable prostaglandins for treating glaucoma. Studies involving isolated esterases and ocular tissue homogenates indicated that 9-acyl esters cannot provide a prodrug since PGF2 alpha would not be formed as a product. In contrast, 11-mono, 15-mono, and 11, 15-diesters were converted to PGF2 alpha in ocular tissues and could, therefore, be considered as prodrugs of PGF2 alpha. Carboxylesterase (CE) appeared critically important for the hydrolytic conversion of those PGF2 alpha prodrugs where the 11 or 15-OH group was esterified and such prodrugs were not substrates for acetylcholinesterase (ACHE) or butyrylcholinesterase (BuCHE). The enzymatic hydrolysis of PGF2 alpha-1-isopropyl ester was also investigated for comparative purposes. This PGF2 alpha prodrug was a good substrate for CE, but was also hydrolysed by BuCHE, albeit at a much slower rate. The most striking feature of the enzymatic hydrolysis of PGF2 alpha-1-isopropyl ester in ocular tissue homogenates was that it was much faster than for prodrugs esterified at the 11 and/or 15 positions. In terms of ocular hypotensive activity, all prodrugs which showed detectable conversion to nascent PGF2 alpha were potent ocular hypotensives. Although no separation of ocular hypotensive and ocular surface hyperaemic effects was apparent for PGF2 alpha-1-isopropyl ester, a temporal separation of these effects was apparent for the novel PGF2 alpha ester series. This difference may reflect an unfavourably rapid conversion of PGF2 alpha-1-isopropyl ester in ocular surface tissues compared with anterior segment tissues.
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PMID:Studies on a novel series of acyl ester prodrugs of prostaglandin F2 alpha. 791 69

1. Due to their involvement in the termination of neurotransmission at cholinergic synapses and neuromuscular junctions, cholinesterases are the target proteins for numerous drugs of neuro-psychopharmacology importance. 2. In order to perform structure-function relationship studies on human cholinesterases with respect to such drugs, a set of expression vectors was engineered, all of which include cloned cDNA inserts encoding various forms of human acetyl- and butyrylcholinesterase. These vectors were designed to be transcribed in vitro into their corresponding mRNA products which, when microinjected into Xenopus oocytes, are efficiently translated to yield their catalytically active enzymes, each with its distinct substrate specificity and sensitivity to selective inhibitors. 3. A fully automated microtiter plate assay for evaluating the inhibition of said enzymes by tested cholinergic drugs and/or poisons has been developed, in conjunction with computerized data analysis, which offers prediction of such inhibition data on the authentic human enzymes and their natural or mutagenized variants. 4. Thus, it was found that asp70-->gly substitution renders butyrylcholinesterase succinylcholine insensitive and resistant to oxime reactivation while ser 425-->Pro with gly70 gives rise to the "atypical" butyrylcholinesterase phenotype, abolishing dibucaine binding. 5. Furthermore, differences in cholinesterase affinities to physostigmine, ecothiophate and bambuterol were shown in these natural variants. 6. Definition of key residues important for drug interactions may initiate rational design of more specific cholinesterase inhibitors, with fewer side effects. This, in turn, offers therapeutic potential in the treatment of clinical syndromes such as Alzheimer's and Parkinson's disease, glaucoma and myasthenia gravis.
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PMID:Structure-function relationship studies in human cholinesterases reveal genomic origins for individual variations in cholinergic drug responses. 827 1

1. The inhibitory effect of N,N,N',N'-tetramethylethylene diamine (TEMED) on water soluble (WSAChE) and membrane bound (MBAChE) acetylcholinesterase was investigated. 2. TEMED (0.5-4.0 mM) reversibly inhibited WSAChE activity (18-62%) and MBAChE (20-61%) in a concentration dependent manner. 3. The IC50 being about 2.8 mM for WSAChE and 2.6 mM for MBAChE. 4. Lineweaver-Burk plots indicated that the nature of inhibition is noncompetitive for both water soluble and membrane bound acetylcholinesterase, with Km values 68 microM and 123 microM respectively. 5. An Arrhenius plot showed that the transition temperature (TT) is unaffected in the presence of TEMED. 6. The activation energy was increased below and above TT in the case of WSAChE only. 7. On the basis of this behaviour of TEMED with AChE, it can be proposed that it can be used as an eluting agent for the bounded AChE to affinity ligand and may have beneficial action on the reactivatability of irreversibly-inhibited AChE due to its structure. 8. Moreover there is a possibility that it can be used as a therapeutic agent for the treatment of Alzheimer's disease, myasthenia gravia and glaucoma like some other inhibitors of AChE.
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PMID:The inhibitory effect of tetramethylethylene diamine on water soluble and membrane bound acetylcholinesterase activity. 846 22


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