4.2.4.2 Cholinergic Agonists: Mode of Binding of Acetylcholine
The acetylcholine molecule is highly flexible, and its preferred conformation is
therefore hard to define. X-ray crystallographic studies suggest that ACh acts as the
gauche conformer, and it is possible to distinguish a “methyl side” and a “carbonyl side,”
corresponding, respectively, to the muscarinic and nicotinic actions of the molecule.
However, this is merely a general approximation, for although the muscarinic activity is
quite specific, steric parameters are rather irrelevant to the action of nicotinic agonists.
It is generally accepted that the ammonium group of ACh binds ionically to a car-
boxylate anion of glutamate or aspartate on the receptor, aided by van der Waals inter-
action of the methyl groups with the adjacent hydrophobic accessory binding site.
About 0.59 nm removed from this, the carbonyl group forms a hydrogen bond with an
acceptor, perhaps with histidine, as in acetylcholinesterase. In muscarinic agonists a
third binding point, involving the methyl group of the acetate, may assume increased
significance. Whereas the primary structural requirements for nicotinic agonists are a
quaternary ammonium and a carbonyl group, the muscarinic agonists are characterized
by an ammonium and a methyl group. The carbonyl group is the primary hydrogen-
binding site in both nicotinic and muscarinic receptors.
Once the drug binds to its receptor it can exert its therapeutic effect. Given the impor-
tance of the cholinergic system both inside and outside of the CNS, it is not surprising
that therapeutic exploitation of cholinergic messenger molecules can be targeted at sys-
temic problems. Cholinergic agonists (cholinomimetics) enjoy widespread use in the
treatment of gastrointestinal and urinary tract problems. In clinical problems involving
reduced smooth muscle activity without obstruction, cholinomimetics with muscarinic
effects may be of use. These clinical problems include postoperative ileus(bowel paral-
ysis following its surgical manipulation) and urinary retention (bladder atony, either
postoperatively or secondary to spinal cord injury [the so-called neurogenic bladder]).
Cholinomimetics, such as bethanechol (4.8), may be used for such disorders. For urinary
tract problems with some degree of obstruction (e.g.,benign prostatic hypertrophy),
α-adrenergic blockade is more effective.
4.2.5 Cholinergic Receptor AntagonistsThe peripheral cholinergic synapses (other than neuromuscular endplates) are mus-
carinic. Drugs that inhibit the interaction of ACh with the AChR are cholinergic block-
ing agents (or parasympatholytics) and must not be confused with the ganglionic and
neuromuscular blocking agents, which act on nicotinic receptors.
Antimuscarinic agents have numerous clinical uses. A heart attack (especially one
affecting the inferior wall of the heart) may depress the electrical system of the heart,
impairing cardiac output. The judicious parenteral use of atropine or some other
antimuscarinic agent may be of value in increasing the heart rate. Antimuscarinics are
widely used for gastrointestinal and genitourinary indications. In the treatment of simple
traveler’s diarrhoea (or other mild, self-limited gastrointestinal hypermotility conditions)
antimuscarinics provide rapid relief; frequently they are combined with an opioid drug
(see chapter 5), which has an additive antiperistaltic effect on bowel motility. Selec-
tive M1 antimuscarinics have some value in the treatment of peptic ulcer disease
212 MEDICINAL CHEMISTRY