Biomedical Engineering Reference
In-Depth Information
The M
2
mAChR is widely expressed in the CNS and in the peripheral nervous system (PNS).
Besides being the far most abundant mAChR in the heart, where it mediates the cholinergic regu-
lation of the heart rate, the M
2
and M
3
receptors are the key subtypes when it comes to the cho-
linergic component of the smooth muscle contraction. In the CNS, M
2
, and the other G
i
-coupled
mAChR, M
4
, function as autoreceptors and heteroreceptors. In contrast to the widespread distri-
bution of M
2
, M
4
is predominantly centrally expressed, and besides its potential as a target for the
treatment of pain, the subtype has been shown to regulate striatal dopamine release.
Similar to the M
2
mAChR, the M
3
subtype is expressed throughout the CNS and the PNS and in
organs innervated by parasympathetic nerves. M
3
knockout mice display a substantial reduction in
body weight due to a reduced food intake compared to wild-type mice, and this phenotype has been
ascribed to their lack of M
3
receptors in hypothalamus, a key brain region for regulation of appetite.
M
1
is the most abundantly expressed mAChR subtype in the forebrain, where it is predominantly
expressed at the postsynaptic termini. Although the M
1
knockout mice do not exhibit signii cantly
impaired cognitive impairment, substantial pharmacological evidence indicate that the receptor is
involved in cognitive processes underlying learning and memory. Furthermore, M
1
knockout mice
exhibit epileptic symptoms, and inhibition of the receptor could hold prospects in the treatment of
Parkinson's disease. The i fth mAChR subtype, M
5
, is expressed in considerably lower levels than
the other mAChRs in both the CNS and PNS.
16.4.1 mAChRA
GONISTS
The compounds
16.26 -16.30
in Figure 16.8 are classical mAChR agonists displaying no signii cant
selectivity for any of the i ve subtypes. Muscarine (
16.26
), which like ibotenic acid and muscimol
(see Chapter 15) is a constituent of
Amanita muscaria
, has dei ned the mAChR family because
of its selectivity for these receptors over the nAChRs. Stabilization of the ester moiety of ACh as
a carbamate group yields carbachol (
16.27
), which not only is nonselective when it comes to the
mAChRs but also is equipotent as a nAChR agonist. The naturally occurring heterocyclic agonist
pilocarpine (
16.28
) is widely used as topical miotic for the control of elevated intraocular pressure
associated with glaucoma. However, the bioavailability of pilocarpine is low, and the compound
does not appear to penetrate the BBB. The potent agonist oxotremorine (
16.29
) has been used exten-
sively as a lead compound for structure-activity studies giving rise to a plethora of mAChR ligands
spanning the entire efi cacy range from full agonists over partial agonist to antagonists.
Because of the high expression levels of the postsynaptic M
1
mAChRs in the brain regions
affected in AD, substantial medicinal chemistry efforts have been put into the development of
agonists selectively targeting this subtype. Arecoline (
16.31
), a constituent in areca nuts (the seeds
of
Areca catechu
), is a cyclic “reverse ester” bioisostere of ACh, containing a tertiary amino group.
16.31
is only partially protonated at physiological pH, which is an advantage in terms of BBB
penetration and CNS availability. A considerable number of analogs of
16.31
have been developed,
including xanomeline (
16.32
), where the labile ester moiety of
16.31
has been replaced with the
more metabolically stable thiadiazole.
16.32
has become the prototypic “M
1
selective agonist”
but in functional assays the compound only exhibits a preference for M
1
over the other subtypes.
In support of this, the
in vitro
proi le of
16.32
has not been translated into an acceptable safety
margin in patients, and due to cholinergic side effects clinical development of the compound for
treatment of AD has been discontinued. Interestingly, in these clinical trials
16.32
have been
found to improve the behavioral disturbances and hallucinations often observed in AD patients,
an effect that subsequently has been ascribed to an effect on dopaminergic signaling via the M
4
subtype. Several other “M
1
-selective/preferring” agonists, including
16.33 -16.35
, have been in
development for the treatment of AD but most of them have been faced with serious cholinergic
side effects in their clinical development, suggesting that they might not be sufi ciently subtype-
selective. AC-42 (
16.36
) is a partial M
1
agonist identii ed in a high-throughput screening, and it bears
no signii cant structural resemblance with ACh or other orthosteric mAChR ligands (Figure 16.8).
