Discovery and Development of Muscarinic Acetylcholine M₄ Activators as Promising Therapeutic Agents for CNS Diseases

Abstract

Among the muscarinic acetylcholine receptor (mAChR) subtypes, the M 4 receptor has been investigated as a promising drug target for the treatment of schizophrenia. These investigations have been based on findings from M 4 -deficient mice studies as well as on the results of a clinical trial that used xanomeline, an M 1 /M 4 mAChRs-preferring agonist. Both orthosteric agonists and positive allosteric modulators of M 4 mAChR have been reported as promising ligands that not only have antipsychotic effects, but can also improve cognitive impairment and motor dysfunction. However, challenges remain due to the high homology of the orthosteric binding site among all muscarinic receptors. In this review, we summarize our approach to the identification of M 4 mAChR activators, orthosteric agonists, and positive allosteric modulators based on M 4 mAChR structural information and structure-activity relationship studies. These findings indicate that selective M 4 mAChR activators are promising potential therapeutic agents for several central nervous system conditions.

Euonymus alatus Twig Extract Protects against Scopolamine-Induced Changes in Brain and Brain-Derived Cells via Cholinergic and BDNF Pathways

“…Aging and AD are associated with deficits of ACh due to hydrolysis by acetyl choline esterase at the synaptic site of the brain, therefore, targeting AChE activity is a potential therapeutic approach for memory-enhancing research or AD [ 18 , 19 ]. ACh esterase inhibitors such as donepezil, galantamine, and rivastigmine, are recommended for the treatment of cognitive dysfunction associated with AD, but their application is limited due to their resulting side effects [ 20 , 21 , 22 ]. This necessitates the development of safe and natural therapeutic products for the treatment of AD.…”

Discovery of Selective M4 Muscarinic Acetylcholine Receptor Agonists with Novel Carbamate Isosteres

“…Modification of the M1/M4 dual agonist 3 , such as through introduction of a quarternary methyl group at the 4-position of piperidine, led to the highly M4 mAChR selective agonist 6 , which exhibited little agonist activity against M1–M3 and M5. This was highlighted in a recent review by Takai . The structural elements required for M1 agonist activity were also studied and reported in our recent publication .…”

“…This was highlighted in a recent review by Takai. 17 The structural elements required for M1 agonist activity were also studied and reported in our recent publication. 18 However, the information on key structural elements for M4 subtype specific activation is still limited since the so-far reported M4 agonists, either M1/ M4 dual, M4-preferred, or M4-selective, all share highly similar chemical features: a basic piperidine core and a terminal ethyl carbamate moiety.…”

Anisodine hydrobromide alleviates oxidative stress caused by hypoxia/reoxygenation in human cerebral microvascular endothelial cells predominantly via inhibition of muscarinic acetylcholine receptor 4

“…M3-mAChR also activates the anti-apoptotic signaling cascades, enhancing the endogenous antioxidant capacity, and diminishing the intracellular Ca 2+ overload, contributing to protecting the heart against ischemic injuries (Liu et al, 2011). M4-mAChR has anti-psychotic effects in the central nervous system, and improves cognitive impairment and motor dysfunction (Takai and Enomoto, 2018). M5-mAChR is located mainly in the substantia nigra, ventral tegmental area, cerebral cortex, and the striatum area of the central nervous system.…”