| Summary: |
Acetylcholine
(ACh) is a neurotransmitter that is hydrolyzed by the enzyme cholinesterase
into chlorine and acetic acid. ACh is expressed at all autonomic ganglia,
automomic nervous system, sweat glands, sympathetic automomic nervous
system, neuromuscular junction between the motor nerve and skeletal
muscle, the interneuron in the CNS, and so forth. ACh’s action
is mediated by two family of receptors, muscarinic ACh receptors (mAChRs)
and the nicotinic ACh receptors (nAChRs). For example, during neurotransmission,
ACh released from the nerve goes to the synaptic cleft and then binds
to ACh receptors (muscarinic and nicotinic) on the postsynaptic membrane. |
| ACh accumulation may be caused by various inhibitors,
which may lead to enzyme inactivation and hyperstimulation of the
muscarinic and nicotinic receptors. However, ACh concentrations may
decrease with age, resulting in sporadic lapses of short-term memory
referred to as age-associated memory impairment. In Alzheimer’s
disease (AD), in contrast, there is a serious brain disorder in which
the ACh levels can drop up to 90%. The drop in ACh levels may also
be caused by intracellular neurofibrillary tangles and extracellular
beta amyloid patched in the ACh pathways of the brain. |
| There is large body of evidence that suggest that basal
forebrain cholinergic neurons and basalo-cortical cholinergic pathways
are degenerated during AD. Consequently, ACh inhibitors may provide
improvements in cognitive and psychiatric symptoms in AD. |
| The muscarinic ACh receptors, a G protein-coupled receptor
superfamily, are prevalent throughout the body and have five distinct
muscarinic receptors (M1–M5), which have been identified in
mammals. The M4 muscarinic ACh receptor predonminantly expressed in
the striatum and in the cortex and hippocampus play a critical role
in mediating higher cognitive processing and in controlling dopamine
release. A nonselective muscarinic antagonist may induce cognitive
deficits and psychosis. Consequently, mAChR activation may provide
pro-cognitive and antipsychotic efficacy. |
| The development of selective M4 positive allosteric modulators (PAMs)
may overcome the challenges of developing selective orthosteric muscarinic
agonists, and selective activation of M4 mAChR may reverse both hyperdopaminergic
and hypoglutamatergic symptoms. The present invention may be useful
in the treatment of AD and other diseases related to the muscarinic
M4 mAChR. |
| Important Compound Classes: |
 |
| Key Structures: |
The inventors
described synthetic procedures and listed structures of over 375 compounds
of Formula (I) including the following representative examples:
|
| Recent Review Articles: |
Corsi-Zuelli F. M.; Brognara F.; Quirino G. F.; Hiroki C. H.; Fais R. S.; Del-Ben C. M.; Ulloa L.; Salgado H. C.; Kanashiro A.; Loureiro C. M.. Frontiers in Immunology 2017, 8618. |
| Xia M.; Cheng X.; Yi R.; Xiong J.; Gao D.. Molecular Neurobiology 2016, 53, 455–471. |
| Shen J.; Wu J.. International Review of Neurobiology 2015, 124275–92. |
| Deardorff W. J.; Shobassy A.; Grossberg G. T.. Expert
Review of Neurotherapeutics 2015, 15, 7–17. |
| Russo P.; Kisialiou A.; Moroni R.; Prinzi G.; Fini M.. Current Drug Targets 2017, 18, 1179–1190. |
| Korczyn A. D.; Zadori D.; Veres G.; Szalardy L.; Klivenyi P.; Toldi J.; Vecsei L.. Journal of Alzheimer’s Disease 2014, 42 ( (Suppl. 3), ), S177–S187. |
| Biological Assay: |
The assay measures
the intrinsic activity of test compounds as modulators of M4 muscarinic
acetylcholine receptor. In this assay, frozen CHO-K1 cells stable
with the human M4 receptor and chimeric G-protein are thawed and then
resuspended in growth medium and then incubated. For a given test,
the growth medium is removed, and cells are washed with buffer, then
incubated in dye loading buffer. Afterward, the cells are placed in
a fluorometric imaging plate reader (FLIPR), and the dye fluorescence
is monitored while the test substance is added at increasing concentrations.
The acetylcholine is also added, and the fluorescence readings are
measured. |
| Biological Data: |
The biological data obtained from testing the above representative
compounds of Formula (I) are listed in the following table:
|
| Claims: |
20 Total claims |
| 13 Composition of
matter claims |
| 7 Method of use claims |
