the same response as does ACh—a brief contraction of the muscle—which, however, is
followed by a prolonged period of transmission blockage accompanied by muscular
paralysis. A related compound, succinylcholine (3.25, succamethonium), has the same
N+–N+distance, even though the ten intervening atoms are not all carbon. It has a short,
self-limiting action since it is easily hydrolyzed by serum cholinesterase. Besides depo-
larizing muscle, both compounds depolarize autonomic ganglia.
The structure–activity relationships of neuromuscular blocking agents are instruc-
tive. The most interesting aspect of these correlations is that between the N+–N+dis-
tance and the receptor structure. As the number of atoms between the -onium groups is
increased beyond 10, the activity decreases until a second peak is reached at around the
16-atom distance (hexacarbacholine (4.26) and related compounds), which corresponds
to a distance of about 2 nm. It is not necessarily the N+–N+distance that is essential; any
induced positive charge will be appropriate. The p-nitrobenzyl-hexamethonium
chloride derivative (4.27), for instance, carries the positive charge on its two phenyl rings
rather than on formal cationic ammonium ions; this is due to the electron-attracting nitro
groups of this compound, which, together with the ammonium ions, dramatically
decrease the π-electron density of the rings. The induced charge distance increases to
about 2 nm, and the hexamethonium derivative is therefore inactive as a ganglionic
blocker but becomes a very effective curarizing agent. It is interesting to note that lower
invertebrates (cladocerans, annelid worms, rotifers) are more sensitive to compounds
with an N+–N+distance of 16 than those with an N+–N+distance of 10, whereas in animals
of phylogenetically higher taxa, such as mammals, this sensitivity is reversed.
The nicotinic AChRs in the ganglion cell and in the neuromuscular endplate are dif-
ferent. The difference probably consists of dissimilar accessory sites. In addition, the
neuromuscular site can accommodate not only compounds with an N+–N+distance of
10 atoms but also those with an N−–N+distance of 16 atoms.
4.2.6 The Clinical–Molecular Interface: Alzheimer’s
Dementia as a Cholinergic DisorderAlzheimer’s disease is a common neurological disorder affecting approximately 20% of
persons over the age of 80 years. Clinically, Alzheimer’s is characterized by loss of
short-term memory, impaired cognition, decline in intellectual function, and decreased
ability to carry out the activities of daily life. At the gross anatomical level, Alzheimer’s
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