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 effect of Soman, Sarin and Vx, known potent cholinesterase inhibitors, on the binding of several neurotransmitter receptors in various regions of brain was studied. Vx, exhibited considerable inhibition of binding of 3H-N-methylscopolamine (3H-NMS) to muscarinic receptors and of 3H-spiperone to dopamine D2 receptors in the striatum. 3H-NMS binding was 50% inhibited at 10(-6)M and 90% at 10(-3)M Vx. Inhibition of 3H-spiperone binding by Vx in striatum had an ID50 of 10(-5)M. KD of the treatment was affected more than Bmax. Binding inhibition of both 3H-NMS and 3H-spiperone in post-mortem brain of rats pre-treated with Vx confirmed the specificity of the organophosphates effect, since other organophosphates and ligands failed to show any activity.
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PMID:Effect of organophosphates on dopamine and muscarinic receptor binding in rat brain. 214 Dec 56

1. Male weanling swine were injected daily for up to 14 days with the organophosphate cholinesterase inhibitors, diisopropylfluorophosphate (DFP) or sarin. The clinical signs of poisoning disappeared or were attenuated by 7 days after starting the DFP treatment, indicating the development of tolerance to DFP toxicity. 2. A significant decrease in acetylcholinesterase activity (85-98%) occurred over the course of this treatment followed by a decrease in the maximal density (Bmax) of [3H] quinuclidinyl benzilate ([3H]QNB) and [3H] N-methylscopolamine ([3H]-NMS) binding sites in isolated cells. The affinity of the muscarinic receptors (KD) for [3H]QNB and [3H]NMS binding, however, remained unaffected. 3. Dose-response curves for ACh-induced increase in isometric tension of tracheal smooth muscle (TSM) showed a leftward shift from control, 2 h after DFP injection. Twenty-four hours after the last DFP treatment, for animals receiving 1 or up to 14 daily injections of DFP, all the dose-response curves were shifted to the left to approximately the same ACh sensitivity when compared with that for control tissue. 4. In vitro treatment of the muscle with 10(-4) M DFP shifted the dose-response curves leftward, in both control and injected animals, and rendered the muscles from control, 1- and 3-day injected animals sensitive to ACh concentrations as low as 10(-10) M. Sensitivity to 10(-10) M ACh was eliminated by carefully cleaning the smooth muscle of adherent connective tissue containing nerves and ganglia and after subacute treatment of swine for 7 days with DFP. DFP-induced spontaneous contractions were also eliminated by careful cleaning. 5. Subacute DFP treatment caused a small leftward shift in the dose-response curve for bethanechol at 2 h and a rightward shift at 1,3 and 7 days, compared to controls. 6. Dose-response curves for K+ were shifted to the right after 1 and 3 days of DFP treatment, but shifted back towards the control after 7 days of treatment. The muscle cells were hyperpolarized by approximately 5 mV after 7 days of DFP or sarin injections. The membrane potential was slightly more sensitive to changes in K+ concentration after 7 days of sarin injection. 7. Subacute treatment of swine with organophosphates modifies the response of neural elements in swine TSM to ACh. Chronic cholinesterase inhibition causes a reduction in the sensitivity of the neural elements to ACh. The decrease in muscarinic receptor density which occurs with chronic cholinesterase inhibition is not sufficient to explain tolerance to organophosphates since TSM maintains an almost normal responsiveness to ACh.
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PMID:Contractile responses of tracheal smooth muscle in organophosphate-treated swine: 1. Agonist changes. 290 99

The properties of muscarinic acetylcholine receptors (mAChR) on tracheal explants and isolated submucosal gland cells were determined using [3H]quinuclidinyl benzilate ([3H]QNB) and N-[3H]methylscopolamine ([3H]NMS) as ligands. Analysis of competitive displacement of ([3H]NMS binding by pirenzepine demonstrated the presence of M1- (27 +/- 2%) and M2G- (73 +/- 2%) receptors on isolated tracheal submucosal gland cells (TSGC's) in control. Daily administration of diisopropylfluorophosphate (DFP) inhibited cholinesterase activity by greater than 95%. After 7 days of DFP treatment, [3H]QNB binding to intact TSGC's decreased from 14.2 +/- 0.6 to 6.3 +/- 0.8 fmol/10(6) cells; similarly, [3H]NMS binding fell from 8.1 +/- 1.9 to 2.0 +/- 0.8 fmol/10(6) cells. The loss of mAChR's was predominantly of the M2G subtype with the relative proportion dropping to 33%. In addition, 90% of the receptors assumed the high-affinity state for carbachol displacement of [3H]NMS. Mucus secretion was quantitated by measuring the release of 3H-labeled mucus macromolecules from explants of tracheal submucosal glands and isolated cells. Acetylcholine (ACh), 2 X 10(-5) M, stimulated mucus secretion by 2.5 and 2.3 times the basal rate, respectively. Elimination of acetylcholinesterase (AChe) by DFP increased the ACh sensitivity by 18- and 5-fold. Tracheal explants or TSGC's obtained 2 h after an in vivo DFP treatment showed a 6- and 3-fold ACh stimulation. This ACh sensitivity decreased during the continued daily dosing with DFP such that only a 1.3- and 1.1-fold ACh stimulation was apparent after 7 days of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Muscarinic stimulation of submucosal glands in swine trachea. 335 38

1. The inhibitory effects of methylene blue (MB) on different types of cholinesterases and [3H]-N-methylscopolamine ([3H]-NMS) binding to muscarinic receptors were studied. 2. Human plasma from young healthy male volunteers, purified human pseudocholinesterase and purified bovine true acetylcholinesterase were incubated with acetylcholine and increasing concentrations of MB (0.1-100 mumol l-1) in the presence of the pH-indicator m-nitrophenol for 30 min at 25 degrees C. The amount of acetic acid produced by the enzymatic hydrolysis of acetylcholine was determined photometrically. 3. Rat cardiac left ventricle homogenate was incubated with [3H]-NMS and with increasing concentrations of MB (0.1 mmol l-1 mumol l-1) at 37 degrees C for 20 min. THe binding of [3H]-NMS to the homogenate was quantified by a standard liquid scintillation technique. 4. MB inhibited the esterase activity of human plasma, human pseudocholinesterase and bovine acetylcholinesterase concentration-dependently with IC50 values of 1.05 +/- 0.05 mumol l-1, 5.32 +/- 0.36 mumol l-1 and 0.42 +/- 0.09 mumol l-1, respectively. MB induced complete inhibition of the esterase activity of human plasma and human pseudocholinesterase, whereas bovine acetylcholinesterase was maximally inhibited by 73 +/- 3.3%. 5. MB was able to inhibit specific [3H]-NMS binding to rat cardiac left ventricle homogenate completely with an IC50 value of 0.77 +/- 0.03 mumol l-1, which resulted in a Ki value for MB of 0.58 +/- 0.02 mumol l-1. 6. In conclusion, MB may be considered as a cholinesterase inhibitor with additional, relevant affinity for muscarinic binding sites at concentrations at which MB is used for investigations into the endothelial system. In our opinion these interactions between MB and the cholinergic system invalidate the use of MB as a tool for the investigation of the L-arginine-NO-pathway, in particular when muscarinic receptor stimulation is involved.
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PMID:The interaction between methylene blue and the cholinergic system. 929 33

Huperzine A (HUP-A), first isolated from the Chinese club moss Huperzia serrata, is a potent, reversible and selective inhibitor of acetylcholinesterase (AChE) over butyrylcholinesterase (BChE) (Life Sci. 54: 991-997). Because HUP-A has been shown to penetrate the blood-brain barrier, is more stable than the carbamates used as pretreatments for organophosphate poisoning (OP) and the HUP-A:AChE complex has a longer half-life than other prophylactic sequestering agents, HUP-A has been proposed as a pretreatment drug for nerve agent toxicity by protecting AChE from irreversible OP-induced phosphonylation. More recently (NeuroReport 8: 963-968), pretreatment of embryonic neuronal cultures with HUP-A reduced glutamate-induced cell death and also decreased glutamate-induced calcium mobilization. These results suggest that HUP-A might interfere with and be beneficial for excitatory amino acid overstimulation, such as seen in ischemia, where persistent elevation of internal calcium levels by activation of the N-methyl-D-aspartate (NMDA) glutamate subtype receptor is found. We have now investigated the interaction of HUP-A with glutamate receptors. Freshly frozen cortex or synaptic plasma membranes were used, providing 60-90% specific radioligand binding. Huperzine A (< or =100 microM) had no effect on the binding of [3H]glutamate (low- and high-affinity glutamate sites), [3H]MDL 105,519 (NMDA glycine regulatory site), [3H]ifenprodil (NMDA polyamine site) or [3H]CGS 19755 (NMDA antagonist). In contrast with these results, HUP-A non-competitively (Hill slope < 1) inhibited [3H]MK-801 and [3H]TCP binding (co-located NMDA ion channel PCP site) with pseudo K(i) approximately 6 microM. Furthermore, when neuronal cultures were pretreated with HUP-A for 45 min prior to NMDA exposure, HUP-A dose-dependently inhibited the NMDA-induced toxicity. Although HUP-A has been implicated to interact with cholinergic receptors, it was without effect at 100 microM on muscarinic (measured by inhibition of [3H]QNB or [3H]NMS binding) or nicotinic [3H]epibatidine binding) receptors; also, HUP-A did not perturb adenosine receptor binding [3H]PIA or [3H]NECA). Therefore, HUP-A most likely attenuates excitatory amino acid toxicity by blocking the NMDA ion channel and subsequent Ca2+ mobilization at or near the PCP and MK-801 ligand sites. Thus, on the one hand, HUP-A could be used as a pretreatment against OPs and it might also be a valuable therapeutic intervention in a variety of acute and chronic disorders by protecting against overstimulation of the excitatory amino acid pathway. By blocking NMDA ion channels without psychotomimetic side-effects, HUP-A may protect against diverse neurodegenerative states observed during ischemia or Alzheimer's disease.
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PMID:The NMDA receptor ion channel: a site for binding of Huperzine A. 1192 Sep 20

In the course of examining the actions of major human bile acids on cholinergic receptors, we discovered that conjugates of lithocholic acid are partial muscarinic agonists. In the present communication, we report that conjugates of deoxycholic acid (DC) act as cholinergic muscarinic receptor antagonists. Chinese hamster ovary (CHO) cells expressing rat M3-muscarinic receptors were used to test bile acids for inhibition of radioligand [N- (3)H-methylscopolamine ((3)H-NMS)] binding; alteration of inositol phosphate (IP) formation; mitogen-activated protein (MAP) kinase phosphorylation and cell toxicity. We observed approximately 18.8, 30.3 and 37.1% inhibition of (3)H-NMS binding with DC and its glycine (DCG) and taurine (DCT) conjugates, respectively (all 100 micromol/l, p < 0.01). DCT and DCG inhibited acetylcholine-induced increases in IP formation and MAP kinase phosphorylation (p44 and p42 ERK). DCG and DCT did not alter trypan blue exclusion or lactate dehydrogenase release from CHO-M3 cells. We observed the following rank order of potency (IC(50) micromol/l) for inhibition of (3)H-NMS by muscarinic antagonists and bile acids: NMS (0.0004) > 4-DAMP (0.009) > atropine (0.012) > DCT (170) > DCG (250). None of the bile acids tested were hydrolyzed by recombinant cholinesterase. At concentrations achieved in human bile, DC derivatives are natural muscarinic antagonists.
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PMID:Deoxycholic acid conjugates are muscarinic cholinergic receptor antagonists. 1211 52

Certain organophosphate (OP) cholinesterase inhibitors (ChEIs) are also known to bind to the muscarinic acetylcholine receptor (mAChR). The functional consequences of such binding were investigated here using the following OP compounds: VX, echothiophate, sarin, and soman. VX (charged at physiological pH) and echothiophate (formally charged) inhibited a specific signal transduction pathway in CHO cells expressing either the M(1) or M(3) mAChR. Hence, they blocked carbamylcholine (CCh)-induced cyclic adenosine monophosphate (cAMP) synthesis (muM) and had almost no effect on CCh-induced phosphoinositide (PI) hydrolysis. These substances were inactive on forskolin-induced cAMP inhibition signaling in CHO cells expressing M(2) mAChR. In binding studies, using [(3)H]-N-methyl scopolamine ([(3)H]NMS) as the competitor ligand, the ChEIs, VX and echothiophate exhibited binding to rat cortical mAChR with K(i) values in the muM range. The non-charged compounds, sarin and soman, were inert in modulating both cAMP metabolism and PI hydrolysis in CHO cells expressing M(1), M(2), and M(3) mAChRs, and no binding was observed in presence of [(3)H]NMS. These data suggest that VX and echothiophate act as function-specific blockers via a non-classical path of antagonistic activity, implying the involvement of allosteric/ectopic-binding site in M(1) and M(3) mAChRs. The functionally selective antagonistic behavior of echothiophate and VX makes them potential tools for dissecting the interactions of the mAChR with different G proteins.
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PMID:Function-specific blockage of M(1) and M(3) muscarinic acetylcholine receptors by VX and echothiophate. 1658 Jun 48