Choline nicotinic receptor agonist

Figure 13.3. An overview of the chemical events at a cholinergic synapse and agents commonly used to alter cholinergic transmission acetyl CoA, acetyl coenzyme A Ch, choline. Nicotine and scopolamine bind to nicotinic and muscarinic receptors, respectively (nicotine is an agonist while scopolamine is an antagonist). Most anti-Alzheimer drugs inhibit the action of the enzyme cholinesterase.

Sir Henry Dale noticed that the different esters of choline elicited responses in isolated organ preparations which were similar to those seen following the application of either of the natural substances muscarine (from poisonous toadstools) or nicotine. This led Dale to conclude that, in the appropriate organs, acetylcholine could act on either muscarinic or nicotinic receptors. Later it was found that the effects of muscarine and nicotine could be blocked by atropine and tubocurarine, respectively. Further studies showed that these receptors differed not only in their molecular structure but also in the ways in which they brought about their physiological responses once the receptor has been stimulated by an agonist. Thus nicotinic receptors were found to be linked directly to an ion channel and their activation always caused a rapid increase in cellular permeability to sodium and potassium ions. Conversely, the responses to muscarinic receptor stimulation were slower and involved the activation of a second messenger system which was linked to the receptor by G-proteins. 

Muscarinic Receptor Interactions. Excitatory muscarinic effects, such as temporary stimulation of salivation and stimulation of intestinal peristalsis, were seen with 2-PAM. Atropine-like actions were seen at high concentrations (15-20 mg/kg or more), and, when injected rapidly, 2-PAM caused temporary diplopia (nicotinic block) and loss of accommodation in the eye.Both TMB-4 and 2-PAM blocked bradycardia induced by vagal stimulation. At low concentrations, neither compound affected normal intestinal peristalsis, but they did block peristalsis caused by increased vagal stimulation. TMB-4, 2-PAM, and toxogonin antagonized the effect of acetylcholine, acetyl- -methyl-choline, and other agonists on Isolated guinea pig ileum.62... 

Analysis of the cholinergic effects of galanthamine in a mouse model suggests that galanthamine does not affect choline acetyltransferase, the choline carrier, or agonist binding to the active site of either muscarinic or nicotinic ACh receptors. 

Acetamiprid (Neonicotinoid) (1992) Nippon soda CH, CN 3 / C = N Cl — V-CKl/ N=/ CH3 Nicotinic acetyl-choline receptor agonist... 

Nitenpyram (Nitromethylene neonicotinoid) (1993) Takeda N —a acetyl-choline receptor agonist... 

Qualitatively, choline has the same pharmacological actions as acetylcholine, but it is far less active at most sites (58). However, choline has been reported (34) to be a full agonist at one nicotinic receptor subtype, and at some other nicotinic subtypes it can act as a partial agonist or a coagonist. 

The different combinations of recombinant neuronal nicotinic receptors differ in their sensitivity to agonists. The list of nicotinic agonists is long and consists of both natural compounds such as choline, nicotine, cytisine, lobeline, epibatidine, anabaseine, and synthetic compounds such as tetramethylammo-... 

Methacholine is a choline ester with an added methyl group. This methyl group is conjugated to the portion of the structure that normally would convey specificity for the nicotinic receptor, blocking access to the site. Thus, this agent is a selective muscarinic agonist and has negligible nicotinic activity. 

An important early clue was that 5-methylhistamine (9.59) was an agonist for H2, but not for Hi, receptors. This situation calls to mind the drug metha-choline, which is the )8-methyl derivative of acetylcholine and has all the latter s activity at muscarinic receptors but none at the nicotinic receptors (Section 12.6). It was found that strong H2 agonist activity in derivatives of histamine... 

In an immunochemical approach to learning more about the receptor site, an antibody was prepared against choline phenyl ether 12.86) in the rabbit. Unfortunately, when this antibody was used as a model for nicotinic receptors, it was found unable to distinguish between muscarinic and nicotinic agents, nor between agonists and antagonists (Marlow, Metcalf and Burgen, 1969). 

Choline is a selective alpha agonist at 7-type nicotinic receptor that is neither addictive nor sympathetic. When tested in animals, it had antinociceptive property. 

Acetylcholine. Acetylcholiae (ACh) (1) is a crystalliae material that is very soluble ia water and alcohol. ACh, synthesized by the enzyme choline acetyltransferase (3), iateracts with two main classes of receptor ia mammals muscarinic (mAChR), defiaed oa the basis of the agonist activity of the alkaloid muscarine (4), and nicotinic (nAChR), based on the agonist activity of nicotine (5) (Table 1). m AChRs are GPCRs (21) n AChRs are LGICs (22). 

Some agonists, such as methacholine, carbachol and bethanecol are structurally very similar to ACh (Fig. 6.6). They are all more resistant to attack by cholinesterase than ACh and so longer acting, especially the non-acetylated carbamyl derivatives carbachol and bethanecol. Carbachol retains both nicotinic and muscarinic effects but the presence of a methyl (CH3) group on the p carbon of choline, as in methacholine and bethanecol, restricts activity to muscarinic receptors. Being charged lipophobic compounds they do not enter the CNS but produce powerful peripheral parasympathetic effects which are occasionally used clinically, i.e. to stimulate the gut or bladder. 

Alkondon M, Pereira EFR, Cortes WS, Maehcke A, Albuquerque EX (1997) Choline is a selective agonist of alpha 7 nicotinic acetylchohne receptors in the rat brain neurons. Eur J Neurosci 9 2734-2742... 

Acetylcholinesterase, the enzyme that hydrolyzes acetylcholine to choline in the postsynaptic membrane, is a serine esterase inhibited by diisopropyl fluorophosphate, sarin, physostigmine, and parathion (Table 11.4). These substances are extremely toxic and cause paralysis. Other toxins block the acetylcholine receptor (antagonists) or lock it open (agonists). Nicotine is an agonist. 

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