ABSTRACT
Another, apparently unsuccessful but
logical approach, was to use direct
replacement of acetylcholine by use of
postsynaptic agonists. The cholinergic system
stimulates both muscarinic and nicotinic
receptors, all of which have multiple isoforms
and some of which are both presynaptic and
postsynaptic. Choosing the target receptor,
therefore, was not an easy task. Blockade of
muscarinic receptors by scopolamine results in
cognitive loss and some muscarinic agonists
have been developed as potential therapies in
AD. Several of these compounds display
preferential activity to the M1 muscarinic
receptor, which has the benefit of reducing the
possibility of adverse events following
peripheral muscarinic agonism. Over a very
short period infusion of a muscarinic agonist
resulted in some cognitive improvements in
patients with AD (Raffaele et al, 1991),
offering some preliminary support for this
approach. The first data from randomized
clinical trials were with Xanomeline – an
M1/M4 agonist. The results showed a small
but significant improvement in cognitive,
behavioural, and global assessments (Bodick et
al, 1997). However, in a subsequent trial
xanomeline showed no effects on the
Alzheimer Disease Assessment Scale (ADAS-
cog) when analysed by the most conservative
intention-to-treat analysis (Veroff et al, 1998)
although completed analysis and analysis of
other cognitive measures did show some
positive and significant benefits from the drug.
