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Chapter: Biochemical Pharmacology : G protein-coupled receptors

Cholinergic agonists

Drugs that stimulate acetylcholine receptors are conven-tionally called `direct agonists', as opposed to `indirect ag-onists', which are inhibitors of acetylcholinesterase (see below).

Cholinergic agonists

Drugs that stimulate acetylcholine receptors are conven-tionally called `direct agonists', as opposed to `indirect ag-onists', which are inhibitors of acetylcholinesterase (see below). Direct cholinergic agonists are used in a variety of clinical applications. Acetylcholine itself is not a very use ful drug because it gets so rapidly hydrolysed. Just like in the experiment above (Figure 9.7), its action in vivo sub-sides as a matter of seconds after discontinuation. Most cholinergic agonists that are in clinical use are partially or completely resistant to degradation by cholinesterase and thus will remain active for extended periods of time.


1. Muscarinic agonists

Two such agonists are shown in Figure 9.9. In the struc-ture of carbamoylcholine, the acetyl group is replaced by a carbamoyl group. This agonist is only very slowly de-graded by cholinesterase. It resembles acetylcholine in being active at both muscarinic and nicotinic synapses. However, the muscarinergic effects are stronger, and car-bamoylcholine is being used clinically to stimulate intesti-nal and urinary bladder motility in transient states of paral-ysis that may occur following surgical procedures. Meta-choline retains the acetyl group; its lower susceptibility to cholinesterase is due to a methyl group that sterically hin-ders the enzyme. The methyl group, at the same time, ren-ders it selectively active on muscarinic synapses. It is used for the same purposes as carbamoylcholine.

Both carbamoylcholine and metacholine are esters and as such highly susceptible to less specific esterases in the intes-tine and liver, so that they cannot be applied orally. Other cholinergic agonists, however, do not possess an ester bond at all, and many of those are indeed active after oral appli-cation.


Figure 9.10 shows two agonists that act selectively on mus-carinic synapses: Muscarine (surprise!) and pilocarpine. Both of these compounds have rather remote similarity with each other or with acetylcholine. Muscarine does not have an ester bond and is active orally. It is, however, not used therapeutically – rather, it is a poison found in toad-stool9 and other mushrooms. It will produce the effects – bronchial constriction, hypersalivation, intestinal cramps that can be predicted from the distribution and functional effects of the muscarinergic receptors that were discussed in the preceding chapter.

Pilocarpine, in contrast to muscarine, is being used thera-peutically – mostly for local application to the eye. It will cause both miosis (by action on the sphincter or constrictor muscle of the iris) and accommodation of the eye lens for seeing close, by acting on another (ciliary) muscle. These muscle movements will decongest a tiny canal which is lo-cated right behind the ciliary muscle10 and thereby facilitate the efflux of fluid from the eye. Pilocarpine is thus used in glaucoma, a disease that is caused by pathologically in-creased pressure within the eye.


Pilocarpine is also used orally – not in clinical medicine, but by some natives of South America, who for some rea-son appear to appreciate the salivation it induces and chew the leaves of the shrub that contain it. It does not seem to cause major toxic effects by ingestion – possibly it is again unstable in the intestine because of its internal ester (lac-tone) bond. However, I assume that it can be taken up to some extent across the mucous membranes.


2. Nicotinic agonists


Nicotine and lobeline (Figure 9.11) are as well found in plants. Both act as agonists on nicotinic synapses, and they share the feature of being fairly hydrophobic. The amino groups in both of them are tertiary rather than quaternary, so that both are capable of non-ionic diffusion, enabling them to pass across membrane barriers. With nicotine, this is apparent in its effect on the central nervous system (along with that upon the peripheral autonomic ganglia). In addi-tion, nicotine is also used in plasters and chewing gums11 by those who want to quit smoking, which is evidence that it can cross mucous membranes and even the skin with ease. In contrast to nicotine, dimethylpiperazinium has a quater-nary amino group. It is therefore permanently ionic and does not easily cross the blood-brain barrier. It does not have any clinical applications I'm aware of, but it is used in research with experimental animals for selective stimula-tion of the autonomic ganglia in the absence of simultane-ous central effects.

The peripheral autonomic effects of nicotine and similar agents are somewhat irregular, due to the fact that both sympathetic and parasympathetic ganglia are stimulated, which will result in partially antagonistic actions. How-ever, in general, the effects on the intestine will be main-ly parasympathetic, which can be nicely observed in small boys smoking their first cigars. Conversely, the effect on the cardiovascular system is predominantly sympathetic, which may be related to the fact that not only the ganglia but also the adrenal glands are being stimulated. With the dosages that are required for the autonomic effects, the functional changes at the motor endplate (= neuromuscular synapse) are irrelevant; at very high concentrations, depo-larizing blockade (see later) may be induced.

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