Nicotinic acetylcholine receptor, inhibitor

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. 

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. 

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. 

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... 

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. 

Hess GP, Gameiro AM, Schoenfeld RC, Chen Y, Ulrich H, Nye JA, Caroll FI, and Ganem B, Reversing the action of non-competitive inhibitors (MK-801 and cocaine) on a protein (nicotinic acetylcholine receptor) mediated reaction, Biochemistry, 42 6106-6114, 2003. 

Mode of action Chitin synthesis inhibitor Electron transport inhibitor Rapid excitation of nervous system by persistent activation of nicotinic acetylcholine receptors Auxin transport inhibitor... 

Rao, K.S., Aracava, Y., Rickett, D.L., Albuquerque, E.X. (1987). Noncompetitive blockade of the nicotinic acetylcholine receptor-ion channel complex by an irreversible cholinesterase inhibitor. J. Pharmacol. Exp. Ther. 240 337-44. 

Onchidal is an irreversible inhibitor of enzyme AChE with a novel mechanism of action. It has been suggested, however, that its toxicity could be a consequence of the inhibition of either nicotinic acetylcholine receptor or AChE enzyme. 

KYNA acts both, as a blocker of the glycine coagonistic site of the NMDA receptor (Kessler et al., 1989) and as a non-competitive inhibitor of the a7 nicotinic acetylcholine receptor (Hilmas et al., 2001). 

Herz, J.M. Atherton, S.J. Steric factors limit access to the non-competitive inhibitor site of the nicotinic acetylcholine receptor. Fluorescence Studies. Biophys. J. 1992, 62, 74—76. 

Carbamazepine is both an important anticonvulsant in therapeutic doses and a powerful proconvulsant in overdose. The therapeutic anticonvulsant mechanism is primarily related to blockade of presynaptic voltage-gated sodium channels. Blockade of the sodium channels is believed to inhibit the release of synaptic glutamate and possibly other neurotransmitters. Carbamazepine is also a powerful inhibitor of the muscurinic and nicotinic acetylcholine receptors, N-methyl-D-aspartate (NMDA) receptors and the central nervous system (CNS) adenosine receptors. In addition, carbamazepine is structurally related to the cyclic antidepressant impramine and in massive overdose may affect cardiac sodium channels. 

---