Acetylcholine inhibitors

Effects Competitive acetylcholine inhibitor at receptor site (postganglionic junction). Does not prevent acetylcholine liberation. Hallucinogen, similar to scopolamine, but producing more excitement and less stupor. Potentiates other psychotropics, including opium, cannabis, harmala alkaloids, mescaline. 

The EMMIA system was developed by Ngo and Lenhoff (N3, N4). In this assay, enzyme activity is modulated by an enzyme modulator which is coupled to antigen (free form) but not by the complex of enzyme modulator-antigen and antibody (bound form). As shown in Fig. 2 and Table 6, in an enzyme inhibitor immunoassay, an enzyme inhibitor is used as a negative modulator. For example, the reaction mixture for measuring thyroxine consists of acetylcholine inhibitor-thyroxine conjugate [I-Ag], acetylcholinesterase [E], unlabeled thyroxine [Ag], and antithyroxine antibody [Ab]. When the amount of unlabeled thyroxine, which binds to antibody [Ab Ag], is increased, the free form of acetylcholine inhibitor-thyroxine conjugate [I-Ag] increases, and the enzyme activity decreases. Therefore, the enzyme activity is inversely proportional to the concentration of unlabeled thyroxine. A tetrazyme kit (Abbott) is now available for measuring thyroxine. 

Category Acetylcholine inhibitor Neuromuscular blocker Half-life 3-6 months... 

The therapeutic use is (like pilocarpine) to decrease the intraocular pressure in the eye in glaucoma. Furthermore, intestinal peristalsis is stimulated and physostigmine is used to remove intestinal atonia after operations. The effect of physostigmine on striated muscles is also important. As an acetylcholine inhibitor physostigmine (and synthetic analogues) is used in the treatment of myasthenia gravis and as an antidote in the case of overdosage of tubocurarine used as a muscle relaxant in complete anaesthesia. 

The other key component of interneuron commmiication is that the neurotransmitters, once they have carried a signal across a synaptic cleft, must be removed. If a receiving neuron is continually stimulated because nemo-transmitters continue to activate it, the neuron s fimction will be impaired, and the neuron may even be killed. There are special enzymes in the synaptic cleft that break down certain neurotransmitters, such as acetylcholine, to end the signaling. Some neurotoxins block the actions of these hydrolytic enzymes, thereby preventing the removal of acetylcholine (or other neurotransmitters), leading to continuous stimulation of the neurons and, ultimately, cell death, see also Acetylcholine Inhibitors Neurotransmitters. 

Clavulazine is an alkaloid of pyrazine that has been identified in the stoloniferan Clavularia viridis, and the gorgonaceans Villagorgia rubra and Eunicdla granulata from Madeleine Islands, Senegal, yielded some rare examples of indole alkaloids. Among them, villagorgins A and B are acetylcholine inhibitors. 

Application of the CCM to small sets (n < 6) of enzyme inhibitors revealed correlations between the inhibitory activity and the chirality measure of the inhibitors, calculated by Eq. (26) for the entire structure or for the substructure that interacts with the enzyme (pharmacophore) [41], This was done for arylammonium inhibitors of trypsin, Di-dopamine receptor inhibitors, and organophosphate inhibitors of trypsin, acetylcholine esterase, and butyrylcholine esterase. Because the CCM values are equal for opposite enantiomers, the method had to be applied separately to the two families of enantiomers (R- and S-enantiomers). 

Mode of Action. All of the insecticidal carbamates are cholinergic, and poisoned insects and mammals exhibit violent convulsions and other neuromuscular disturbances. The insecticides are strong carbamylating inhibitors of acetylcholinesterase and may also have a direct action on the acetylcholine receptors because of their pronounced stmctural resemblance to acetylcholine. The overall mechanism for carbamate interaction with acetylcholinesterase is analogous to the normal three-step hydrolysis of acetylcholine however, is much slower than with the acetylated enzyme. 

An enzymatic assay can also be used for detecting anatoxin-a(s). " This toxin inhibits acetylcholinesterase, which can be measured by a colorimetric reaction, i.e. reaction of the acetyl group, liberated enzymatically from acetylcholine, with dithiobisnitrobenzoic acid. The assay is performed in microtitre plates, and the presence of toxin detected by a reduction in absorbance at 410 nm when read in a plate reader in kinetic mode over a 5 minute period. The assay is not specific for anatoxin-a(s) since it responds to other acetylcholinesterase inhibitors, e.g. organophosphoriis pesticides, and would need to be followed by confirmatory tests for the cyanobacterial toxin. 

Eda and Kurth applied a similar solid-phase combinatorial strategy for synthesis of pyridinium, tetrahydropyridine, and piperidine frameworks as potential inhibitors of vesicular acetylcholine transporter. One member of the small library produced was prepared from amino-functionalized trityl resin reacting with a 4-phenyl Zincke salt to give resin-bound product 62 (Scheme 8.4.21). After ion exchange and cleavage from the resin, pyridinium 63 was isolated. Alternatively, borohydride reduction of 62 led to the 1,2,3,6-tetrahydropyridine 64, which could be hydrogenated to the corresponding piperidine 65. 

CBs, like OPs, act as inhibitors of ChE. They are treated as substrates by the enzyme and carbamylate the serine of the active site (Figure 10.8). Speaking generally, car-bamylated AChE reactivates more rapidly than phosphorylated AChE. After aging has occurred, phosphorylation of the enzyme is effectively irreversible (see Section 10.2.4). Carbamylated AChE reactivates when preparations are diluted with water, a process that is accelerated in the presence of acetylcholine, which competes as a substrate. Thus, the measurement of AChE inhibition is complicated by the fact that reactivation occurs during the course of the assay. Carbamylated AChE is not reactivated by PAM and related compounds that are used as antidotes to OP poisoning (see Box 10.1). 

Inhibitors of enzyme causing buildup of acetylcholine in synapses... 

Acetylcholinesterase is a component of the postsynaptic membrane of cholinergic synapses of the nervous system in both vertebrates and invertebrates. Its structure and function has been described in Chapter 10, Section 10.2.4. Its essential role in the postsynaptic membrane is hydrolysis of the neurotransmitter acetylcholine in order to terminate the stimulation of nicotinic and muscarinic receptors (Figure 16.2). Thus, inhibitors of the enzyme cause a buildup of acetylcholine in the synaptic cleft and consequent overstimulation of the receptors, leading to depolarization of the postsynaptic membrane and synaptic block. 

Peptides in the a-conotoxin family are inhibitors of nicotinic acetylcholine receptors. They were first isolated from C. geographus venom as components which cause paralysis in mice and fish when injected intraperitoneally (27). Early physiological experiments (28) indicated that a-conotoxins GI, GII, and GIA (see Table III) all act at the muscle end plate region. Mini end-plate potentials and end plate potentials evoked in response to nerve stimulation are inhibited in the presence of a-conotoxins in the nM to pM range. a-Conotoxin GI was subsequently shown to compete with rf-tubocurarine and a-bungarotoxin for the acetylcholine receptor (29). 

Katz E, WiUner 1, Wang J (2004) Electroanalytical and bioelectroanalytical systems based on metal and semiconductor nanoparticles. Electroanalysis 16 19-44 Pardo-Yissar V, Katz E, Wasserman J, Willner 1 (2003) Acetylcholine esterase-labeled CdS nanoparticles on electrodes Photoelectrochemical sensing of the enzyme inhibitors. J Am Chem Soc 125 622-623... 

Galantamine is a ChE inhibitor, which elevates acetylcholine in the cerebral cortex by slowing the degradation of acetylcholine.37 It also modulates the nicotinic acetylcholine receptors to increase acetylcholine from surviving presynaptic nerve terminals. In addition, it may increase glutamate and serotonin levels. The clinical benefit of action of these additional neurotransmitters is unknown. 

Both the G- and V-agents have the same physiological action on humans. They are potent inhibitors of the enzyme acetylcholinesterase (AChE), which is required for the function of many nerves and muscles in nearly every multicellular animal. Normally, AChE prevents the accumulation of acetylcholine after its release in the nervous system. Acetylcholine plays a vital role in stimulating voluntary muscles and nerve endings of the autonomic nervous system and many structures within the CNS. Thus, nerve agents that are cholinesterase inhibitors permit acetylcholine to accumulate at those sites, mimicking the effects of a massive release of acetylcholine. The major effects will be on skeletal muscles, parasympathetic end organs, and the CNS. 

Caffeine increases the effect of acetylcholine or cholinesterase inhibitors. 

The toxic organic phosphorus compounds act as powerful inhibitors of cholinesterase, an enzyme found predominantly in the nervous tissue of animals, including insects. This enzyme hydrolyzes acetylcholine, which plays an essential role in the transmission of nerve impulses. The toxicity of compounds in this series can be largely accounted for on the basis of their anticholinesterase activity (7,8,12,14, SI). 

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