mixture of muscarinic M1 receptor agonist and NMDA receptor antagonist
Mode of action:
- muscarinic M1 receptor agonism
- N-methyl-D-aspartate (NMDA) receptor antagonism
AGORA Pharmaceuticals s.r.o.
The results of the latest studies show that selective M1 muscarinic receptor (mAChR) agonists improve cognitive functions in different models of cholinergic dysfunction and in addition they have a strong potential of disease-modification because due to their effects on GSK-3β via PKC they interfere with both, amyloid and tau metabolism. Nowadays, some of them are going through several phases of preclinical studies and their very promising outcomes show that development of such compounds might be beneficial for treatment of Alzheimer’s disease (AD), but also for other types of dementia, associated with cholinergic deficit. For example, compounds AF102B and AF150(S) have been already tested in vitro and in vivo in several animal models of AD with remarkable results. These substances are able to reduce β-amyloid (Aβ) load and increase the non-amyloidogenic amyloid precursor protein (α-APPs) levels in vitro and in vivo. In addition, they inhibit Aβ- and oxidative stress-induced cell death and apoptosis in PC12 cells transfected with the M1 mAChR. Above that, they are neurothrophic and synergistically active with neurothrophins such as nerve growth factor or epidermal growth factor. These drugs also decrease tau hyperphosphorylation in mice possessing small hippocampi and in aged primates Microcebus murinus with high safety margin. They are able to restore cognitive impairment. Moreover, these drugs show high bioavailability and significant preference for the brain vs. plasma following p.o. administration. Therefore, they have a great potential to surpass current standard therapy of AD, which is mostly focused on one target and neglects other major hallmarks of the disorder. Finally, administration of such M1 agonists in combination with other already approved drugs, like memantine, has a potential to protect neurons and modify disease progression. It is most likely that such a combination will exert synergistic effects for treatment of AD. The combination into one formulation will also increase the compliance.
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