Agonists at the cholinergic receptor

One point might have occurred to the reader. If there is a lack of acetylcholine acting at a certain part of the body, why do we not just give the patient more acetylcholine After all, it is easy enough to make in the laboratory (Fig. 11.7). 

Therefore, we need analogues of acetylcholine which are more stable to hydrolysis and which are more selective with respect to where they act in the body. We shall look at selectivity first. 

a synthetic analogue of acetylcholine which is slightly bigger than acetylcholine itself would bind to the latter receptor, but would be unable to bind to the former receptor because of the wall. 

This theory might appear to be wishful thinking, but it is now established that cholinergic receptors in different parts of the body are indeed subtly different. 

This is not just a peculiarity of acetylcholine receptors. Subtle differences have been observed for other types of receptors such as those for dopamine, noradrenaline, and serotonin. 

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Other mechanisms, such as the inhibition of -amyloid formation. There are several other alkaloids which are nicotinic agonists at the cholinergic receptor such as lobeline (89) from Lobelia inflata. Lobelia inflata a could be exploited to influence cholinergic function in AD. Sophoramine (90) and cytisine (91), found in members of the Leguminosae, have nicotinic actions but they do not appear to have been developed for any pharmaceutical purposes, probably because of their toxicity. 

Therefore, an antagonist at the acetylcholinesterase enzyme will have the same biological effect as an agonist at the cholinergic receptor. 

Many compounds structurally related to nicotine have been tested for activity with the nicotinic cholinergic receptor but. as with the (+)- isomer of nicotine, they generally less activity as agonists, while showing other activities such as blocking the ion channel. Metabolic derivatives of nicotine may account for some of the actions attributed to nicotine, but not necessarily actions at the nicotinic receptor [162]. Nicotine does, indeed, act on other tissues and some of these actions will be cited in other sections of this review. 

The ideal agent for facilitating central cholinergic transmisson would act simultaneously as an antagonist at ACh autoreceptors and as an agonist at postsynaptic ACh-receptors.It has been suggestedl B that compounds, with this profile would be of therapeutic value in the... 

When designing a dmg to be a cholinergic agonist, selectivity is highly desirable but not a simple term, as therapeutic candidates should be selective for the cholinergic receptor among other neurological receptors, selective for nicotinic or muscarinic, or selective for spedfic subtypes or tissue types. Selectivity could be achieved on the pharmacodynamic level, where the stmcture of the dmg molecule makes it more active at one receptor than another, or on the pharmacokinetic level where the molecular stmcture of the dmg makes it more available to spedfic tissues. Equally important, the new stmcture should retain ACh s activity (see Box 16.1). 

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.

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