Acetylcholine receptors inhibitors

Anew 6-Cys/4-loop framework (CC—C—-C—C—C) has been reported for three peptides conotoxins pPnIVAand pPnlVB from C pennaceus (Fainzilber et al., 1994) and aA-conotoxin PIVA of Conus purpurascens (Hopkins et al., 1995). pPnlVA and pPnIVB are sodium channel blockers selective for molluscan neurons they have no effect on sodium currents in bovine chromaffin cells and rat brain synaptosomes (Fainzilber et al., 1994). aA-Conotoxin PIVA is an acetylcholine receptor inhibitor. 

Peptides belonging to the same pharmacological class may have different structural frameworks. Indeed, acetylcholine receptor inhibitors may have the Cys/loop framework CC—C—C of a-conotoxins, CC—C—C—C—C of aA-conotoxins or CC—-C— C—C of a-conotoxin SII. The known sodium channel blockers also have three types of structural framework CC— C—C—-CC (p-conotoxins), C—C—CC—C—-C (conotoxin-GS, pO-conotoxins MrVIA and MrVIB) or CC—C—C—C—-C (p-conotoxins PnIVAand PnIVB). 

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. 

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). 

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. 

A retro-l,3-dipolar cycloaddition followed by an 1,3-dipolar cycloaddition was used for a highly efficient total synthesis of (-)-histrionicotoxin (4-354) (HTX) by Holmes and coworkers [123]. HTX is a spiropiperidine-containing alkaloid which was isolated by Doly, Witkop and coworkers [124] from the brightly colored poison-arrow frog Dendrobates histrionicus. It is of great pharmacological interest as a noncompetitive inhibitor of acetylcholine receptors. 

Albuquerque EX, Aracava Y, Cintra WM, Brossi A, Schonenberger B, Deshpande SS. Structure-activity relationship of reversible cholinesterase inhibitors activation, channel blockade and stereospecificity of the nicotinic acetylcholine receptor-ion channel complex. Braz. J. Med. Biol. Res. 21 1173-1196, 1988. 

There are three ways to increase acetylcholine activity (1) increase the supply of acetylcholine, (2) directly stimulate acetylcholine receptors (muscarinic agonists), and (3) block the enzyme that inactivates acetylcholine (cholinesterase inhibitors). Let s take a look at each of these approaches. 

Tubocurarine acts as a competitive inhibitor in the nicotinic acetylcholine receptor, meaning that the nerve impulse is blocked by this alkaloid. Tubocurarine is used in surgical practice as a muscle relaxant. These alkaloids have an observably large spectrum of activity and possible applications. Their utilization in the development of new applications is therefore relatively active in modern medicine. 

The cholinesterase inhibitors can increase activity in both sympathetic and parasympathetic ganglia supplying the heart and at the acetylcholine receptors on neuroeffector cells (cardiac and vascular smooth muscles) that receive cholinergic innervation. 

Cholinesterase inhibitors—but not direct-acting acetylcholine receptor agonists—are extremely valuable as therapy for myasthenia. Patients with ocular myasthenia may be treated with cholinesterase inhibitors alone (Figure 7-4B). Patients having more widespread muscle weakness are also treated with immunosuppressant drugs (steroids, cyclosporine, and azathioprine). In some patients, the thymus gland is removed very severely affected patients may benefit from administration of immunoglobulins and from plasmapheresis. 

Another important example is the nicotinic acetylcholine receptor, which is activated by the agonist nicotine causing muscular fibrillation and paralysis. Indirect effects can also occur. For example, organophosphates and other acetylcholinesterase inhibitors increase the amount of acetylcholine and thereby overstimulate the receptor, leading to effects in a number of sites (see chap. 7). Alternatively, botulinum toxin inhibits the release of acetylcholine and causes muscle paralysis because muscular contraction does not take place (see chap. 7). 

One of the best-understood autoimmune diseases is myasthenia gravis, a condition associated with a decrease in the number of functional post-synaptic nicotinic acetylcholine receptors (Fig. 30-23) in neuromuscular junctions. e The resulting extreme muscular weakness can be fatal. Myasthenia gravis is not rare and affects about one in 10,000 peopled An interesting treatment consists of the administration of physostigmine, diisopropyl-phosphofluoridate (Chapter 12, Section C,l), or other acetylcholinesterase inhibitors (Box 12-E). These very toxic compounds, when administered in controlled amounts, permit accumulation of higher acetylcholine concentration with a resultant activation of muscular contraction. The same compounds... 

Cholinesterase inhibitors—but not direct-acting acetylcholine receptor agonists—are extremely valuable as therapy for myasthenia. Almost all patients are also treated with immunosuppressant drugs and some with thymectomy. 

Arias, H.R. (1996) Luminal and non-luminal non-competitive inhibitor binding sites on the nicotinic acetylcholine receptor. Molec. Membr. Biol., 13, 1. 

Pyrazole-based COX-inhibitors were synthesized using Pd/C as a heterogeneous and ready-filterable palladium source. Electron-deficient boronic acids coupled well while orf/zo-substitulcd and electron-rich boronic acid were less reactive (Scheme 62) [146]. The same team also developed a two-step and one-pot procedure for the synthesis of styrene-based nicotinic acetylcholine receptor antagonists. 

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