Targeting the M1 muscarinic acetylcholine receptor in Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) remains a major cause of morbidity and mortality worldwide, and despite extensive research, only a few drugs are available for management of the disease. One strategy has been to upregulate cholinergic neurotransmission to improve cognitive function, but this approach has dose-limiting adverse effects. To avoid these adverse effects, new drugs that target specific receptor subtypes of the cholinergic system are needed, and the M1 subtype of muscarinic acetylcholine receptor (M1-mAChR) has been shown to be a good target for this approach. By using several strategies, M1-mAChR ligands have been developed and trialled in preclinical animal models and in human studies, with varying degrees of success. This article reviews the different approaches to targeting the M1-mAChR in AD and discusses the advantages and limitations of these strategies. The factors to consider in targeting the M1-mAChR in AD are also discussed.

Role of Muscarinic Acetylcholine Receptors in Intestinal Epithelial Homeostasis: Insights for the Treatment of Inflammatory Bowel Disease

“…Therefore, it is important to determine the effects of subtype-selective agonists and positive allosteric modulators (PAMs) on intestinal epithelial cell homeostasis and their impact on IBD treatment. In particular, M 1 receptor-selective agonists and PAMs are being actively developed as potential therapeutic agents for schizophrenia and Alzheimer’s disease [ 95 , 96 ]. Exploring the potential of these drugs in the treatment of IBD is an interesting challenge.…”

Crosstalk between Adult Hippocampal Neurogenesis and Its Role in Alzheimer’s Disease

“…Acetylcholine (ACh) is one of the important neurotransmitters that play a crucial role in AD pathology and is involved in various biological processes such as attention, learning, memory, stress response, wakefulness and sleep, and sensory information. − Earlier reports indicate that selective activation of muscarinic acetyl choline receptor (mAChR) M1 and M3 but not M2 and M4 enhances αAPPs and diminishes the total Aβ formation. − Inline, first, cholinesterase inhibitors were tested against AD, and tacrine was the first drug approved for senile AD but soon was withdrawn, due to severe side effects …”

Imaging Cholinergic Receptors in the Brain by Positron Emission Tomography

“…Nonetheless, the slow kinetics of [ 18 F]nifzetidine (79) necessitated a prolonged imaging time of greater than 3 h for quantitative PET studies. 195 Further optimization led to the development of 3-(2-(S)-3,4dehydropyrrolinylmethoxy)-5-(3′-[ 18 F]fluoropropyl)pyridine ([ 18 F]nifrolene (80)), which has a binding affinity for α4β2-nAChRs similar to that of 2-[ 18 F]FA (67). 196 In vivo rhesus monkey PET studies of [ 18 F]nifrolene revealed the highest binding in the thalamus followed by regions of the lateral cingulated and temporal cortex and least binding in the cerebellum.…”