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evidenced in the alkaloids related to atropine. M2 antimuscarinic drugs can also have
voluminous substituents on the nitrogen atom, which shows the presence of complementary hydrophobic zones at that level. M2 antimuscarinic dru gs are structurally
classified into aminoalkyl esters, aminopropanols, and amidoammonium derivatives.
The general structures of these drug families are shown in Fig. 1.19. In all cases, the
quaternization of the nitrogen atom leads to compounds devoid of central action.
Fig. 1.19: Structural families and some M2 antimuscarinics.
1.14 Disconnection and syntheses of aminoalkyl esters
In Chapter 8 of Volume 1 of this series, the general principles of disconnections have
been established; however, some concepts will be recalled here, which will be applied
to the rational design of certain M2 antimuscarinic drugs:
– Target molecule is the molecule to be synthesized.
– Retrosynthetic analysis or retrosynthesis is the process of mentally breaking
down a molecule into the starting materials.
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– Disconnection is an imaginary bond cleavage corresponding to a reverse of a real
reaction.
Scheme 1.5 shows the disconnections of the aminoethyl esters anddiphenylacetic
acid, as well as the corresponding synthesis of the latter.
Scheme 1.5: Disconnection and synthesis of diphenylacetic acid.
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1.14.1 Simple alcohol disconnections
Scheme 1.6 shows disconnections of simple alcohols and will subsequently help us to plan
the disconnection and synthesis of the hydroxyacid moiety [2-(1-hydroxycyclopentyl)-2phenylacetic acid] present in cyclopentolate (Scheme 1.7).
Scheme 1.6: Disconnection and synthesis of acetylenic alcohols.
1.14.1.1 Cyclopentolate
Cyclopentolate is commonly used as an eye drop during pediatric eye examinations to
dilate the eye (mydriatic). It is on the World Health Organization’s List of Essential Med-
icines (2021). Disconnection and synthesis of 2-(1-hydroxycyclopentyl)-2-phenylacetic
acid, present in cyclopentolate, are shown in Scheme 1.7.
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Scheme 1.7: Disconnection and synthesis of 2-(1-hydroxycyclopentyl)-2-phenylacetic acid, present in
cyclopentolate.
1.14.2 Aminoesters
Scheme 1.8 shows the disconnection and synthesis of (β-chloroethyl)dialkylamines (a
starting material needed for the preparation of β-amino esters), in addition to the synthesis of piperidolate, as a representative of esters of amino alcohols of heterocyclic
nature.
1.14.3 Aminopropanols
The second group of synthetic antimuscarinic drugs is aminoalcohol s, in which the
ester function has been replaced by a tertiary alcohol. The drugs in this group are
mainly used for the treatment of Parkinson’s disease, that is, as anticholinergics in the
CNS. One of the most characteristic is trihexyphenidyl, which can be prepared from
benzene and cyclohexanecarboxylic acid (Scheme 1.9).
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Scheme 1.8: Disconnection and synthesis of (β-chloroethyl)dialkylamines, and synthesis of piperidolate.
1.15 Amidoammonium drugs
Finally, the third important group of synthetic anticholinergics is the so-called amidoammonium drugs. The most repres entative example is isopropamide, which is a
long-acting anticholinergic drug. It is used in the treatment of peptic ulcers and other
gastrointestinal disorders involving hyperacidity (gastrointestinal a cidosis) and hypermotility. Chemically, it contains a quaternary ammonium ion. It is most often pro-
1.16 Antagonist drugs on nicotinic receptors 23
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Scheme 1.9: Synthesis of trihexyphenidyl.
vided as an iodide salt, but is also available as a bromide or chloride salt. Its synthesis
is shown in Scheme 1.10.
1.16 Antagonist drugs on nicotinic receptors
The first known compound with antagonistic activity on nicotinic receptors of the
neuromuscular junction was tubocurarine chloride (Fig. 1.20), the activ e ingredient
contained in curare, ex tract of the Chondrodendron tomentosum plant, used by the
Amazonian Indians in the hunting arts for its paralyzing properties.
Curare is actually a mixture of compounds, and its active substance (tubocurarine)
was not isolated until 1935. The first structure assigned to tubocurarine possessed two
nitrogen atoms, both of which were quaternary ammonium salts (e.g., a bis-quaternary
ammonium compound). It was not until 1970 that the correct structure was reported.
The correct structure, shown here, has only one quaternary ammonium nitrogen; the
other nitrogen is a tertiary amine salt. Nevertheless, the incorrect structure of tubocurarine served as a model for the synthesis of all the neuromuscular blocking agents in use
today. These compounds have been of immense therapeutic value for surgical procedures. The potential therapeutic benefits of the neuromuscular blocking effects of tubocurarine as well as the difficulty in obtaining pure samples of the alkaloid encouraged
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Scheme 1.10: Synthesis of isopropamide.
Fig. 1.20: Tubocurarine chloride.
medicinal chemists to design structurally related compounds possessing nicotinic antagonist activity.
One problem associated with tubocurarine is the absence of the ester moiety,
which would not explain its robust blocking action on the nicotinic receptor. The
blocking action of tubocurarine, as well as that of synthetic analogs with a double ammonium salt structure, is due to the presence of two cationic centers. They are separated by 1.4 nm (nicotinic distance in the neuromuscular junctions), anchoring the
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molecule to one of the binding sites of ACh and over an accessory zone, in which a
cysteine residue is probably present (Fig. 1.21), located 0.9–1.2 nm away.
Fig. 1.21: Interaction model of the quaternary bis-ammonium derivatives with the nicotinic receptor.
The possibility that the quaternary bis-ammonium derivatives simultaneously bind to
the two subunits of the ionic channel is not feasible because of the great distance between them (8 nm). On the other hand, neither is it possible between subunits of different monomers, since they are separated by a distance of 10 nm. Therefore, it is clear
that the distance between the two positively charged nitrogen atoms is crucial for the
activity. Consequently, analogs that maintain this distance should be good antagonists.
1.16.1 Decamethonium and suxamethonium
Decamethonium (Fig. 1.22) is a simple analog of tubocurarine. It is a linear molecule,
and as such it is capable of achieving a large number of conformations. The fully extended conformation would have the nitrogen atoms separated by a d istance of
1.35 nm, which is analogous to the distance of tubocurarine (1.4 nm).
Fig. 1.22: Decamethonium.
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The drug binds strongly to nicotinic receptors, but has several drawbacks: when it
binds to the ACh receptor, it acts as an agonist rather than an antagonist. In other
words, it activates the receptor, leading to a brief contraction of the muscle. Once this
effect has passed, the drug remains bound to the receptor (blocking access for ACh)
and then acts as an antagonist. Unfortunately, it binds very strongly, and accordingly,
patients take a long time to recover from its effects. It is also not completely selective
for neuromuscular junctions and has effects on the ACh receptors in the heart. This
leads to a decrease in heart rate (bradycardia) and a drop in blood pressure.
As decamethonium is very stable, the introduction of some form of instability
into the drug was considered. This was achieved by introducing ester groups in the
chain, while maintaining the correct distance between both positively charged nitrogen atoms; suxamethonium (Fig. 1.23) was designed in such a way (see Chapter 7 of
Volume 1 of this series).
Fig. 1.23: Suxamethonium or succinylcholine.
The ester groups are susceptible to chemical and enzymatic hydrolysis. Once hydrolysis takes place, the molecule cannot bind to the receptor and becomes inactive. Drugs
designed to be metabolized through a single, nonoxidative pathway are known as soft
drugs. Suxamethonium’s duration of action lasts only 5–10 min, but it has other side
effects on the autonomic ganglia.
1.16.2 Atracurium
The design of atracurium (Fig. 1.24) was based on tubocurarine and suxamethonium
structures. It is superior to both, because it lacks cardiac side effects and rapidly degrades in the blood.
Fig. 1.24: Atracurium.
1.17 Anticholinesterases and acetylcholinesterase 27
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Its rapid degradation allows the drug to be administered intravenously. Rapid degradation was designed by incorporating a self-destructive mechanism. At the pH of
blood (7.4), the molecule can undergo Hofmann’s elimination. Once this occurs, the
compound is deactivated as the positive charge on the nitrogen atom is lost (Fig. 1.25).
Fig. 1.25: Hofmann’s elimination on atracurium.
The characteristics of atracurium are as follows:
– The spacer: This is a chain of 13 atomic units connecting the 2 quaternary centers.
– Blocking units: These are cyclic structures at both ends of the molecule that block
the ACh receptor site.
– Quaternary centers.
– Hofmann’s elimination: This usually requires strong alkaline conditions and high
temperatures. However, if an electron-withdrawing group is present at the β-
carbon in relation to N+ (as is the acetate group), it allows the reaction to proceed
under much milder conditions. The electron-withdrawing group increases the
acidity of the hydrogen atoms in the β-carbon atom so that they are easily lost.
Since the drug on ly acts very briefly, it has to be administered intravenously for as
long as required. As soon as the surgical operation ceases, the drip stops, and the antagonism ceases almost instantaneously. Another advantage of the drug is that it is
deactivated by a chemical mechanism and not by an enzymatic mechanism, so the
deactivation rate is constant across patients.
1.17 Anticholinesterases and acetylcholinesterase
1.17.1 Effect of anticholinesterases
Anticholinesterases are antagonists of the enzyme acetylcholinesterase (the enzyme
that hydrolyzes ACh). If ACh was not destroyed, it could reactivate the cholinergic receptor, so the effect of anticholinesterase would be to increase the ACh levels, with a
consequent increase in the cholinergic effects. Therefore, an acetylcholinesterase enzyme antagonist will have the same biological effect as a cholinergic receptor agonist.
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