M1 muscarinic acetylcholine receptors: A therapeutic strategy for symptomatic and disease-modifying effects in Alzheimer's disease?

The M1 muscarinic acetylcholine receptor (mAChR) plays a crucial role in learning and memory processes and has long been identified as a promising therapeutic target for the improvement of cognitive decline in Alzheimer's disease (AD). As such, clinical trials with xanomeline, a mAChR orthosteric agonist, showed an improvement in cognitive and behavioral symptoms associated with AD. Despite this, the clinical utility of xanomeline was hampered by a lack of M1 receptor selectivity and adverse cholinergic responses attributed to activation of peripheral M2 and M3 mAChRs. More recently, efforts have focused on developing more selective M1 compounds via targeting the less-conserved allosteric binding pockets. As such, positive allosteric modulators (PAMs) have emerged as an exciting strategy to achieve exquisite selectivity for the M1 mAChR in order to deliver improvements in cognitive function in AD. Furthermore, over recent years it has become increasingly apparent that M1 therapeutics may also offer disease-modifying effects in AD, due to the modulation of pathogenic amyloid processing. This article will review the progress made in the development of M1 selective ligands for the treatment of cognitive decline in AD, and will discuss the current evidence that selective targeting of the M1 mAChR could also have the potential to modify AD progression.