These tropine derivatives are esters of tertiary bases with a bulky acid component
(atropic acid, mandelic acid). In general, a number of cholinergic blocking agents have
been developed by substituting a larger acid for the acetyl group of ACh and increasing
the size of the N-substituents. Among the quaternary compounds, tridihexethyl bromide
(4.19) and propantheline bromide (4.20) are notable; among the tertiary amines
oxyphencyclimine (4.21) shows high activity. Numerous analogs are known and are
used therapeutically (e.g., methylatropine and methylscopolamine).
4.2.5.1 Cholinergic Antagonists: Ganglionic Blocking Agents
Ganglionic blocking agents interfere with the nicotinic ACh receptors in the ganglia.
Although ganglia are, functionally, normal receptors, they probably differ structurally
from the receptors at the neuromuscular endplate, and show different accessibility.
Ganglionic and neuromuscular blocking agents are therefore two structurally different
groups of anticholinergic drugs.
Ganglionic blockade by tetraethylammonium salts (4.22) has been known for a long
time; however, the prototype blocking agent is hexamethonium (1.1), a bisquaternary
compound with six methylene groups separating the two cationic groups. Some secon-
dary and tertiary amines such as trimetaphan (4.23) and mecamylamine (4.24) were in
use at one time, since they had longer durations of action in controlling hypertension
by decreasing vasoconstriction. However, because none of these compounds can dis-
tinguish sympathetic from parasympathetic ganglia, they have numerous side effects.
Consequently, they have largely been replaced by the more selective β-adrenergic
blocking agents.
214 MEDICINAL CHEMISTRY