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 up-regulate 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.

Keywords: Alzheimer's disease; acetylcholine; allosteric regulation; muscarinic receptor; orthosteric.

Figure 1. Common signalling transduction pathways of the five subtypes of the mAChR

Activation of M1-, M3- or M5-mAChR results in coupling of the receptor to the G_q/11 family of G proteins. This coupling leads to activation of phospholipase C (PLC) enzyme, with subsequent mobilisation and release of calcium (Ca²⁺) from the intracellular stores to the cytosol. Activation of M2- or M4-mAChR results in coupling to the G_0/I family of G proteins. This coupling leads to inhibition of adenylate cyclase enzyme, which results in decreased levels of cytosolic cAMP.

Figure 2. Allosteric modulation at the M1-mAChR

Binding of a ligand to the allosteric pocket of the M1-mAChR can have three effects. (A) A conformational change in the receptor, leading to a change in the binding affinity of the orthosteric-bound ligand, in this case, ACh for the receptor. (B) A broader conformational change, leading to a change (increase or decrease) in the potency of ACh toward a particular signalling response. (C) A direct agonist effect exerted by the allosteric ligand independent of the presence of the orthosteric-bound ligand, ACh.

Figure 3. Chemical structures of M1-mAChR allosteric ligands developed by Merck

PQCA and MK-7622 are based on the chemical scaffold of BQCA.

Figure 4. Chemical structures of M1-mAChR allosteric ligands developed by Pfizer

PF06827443 and PF-06764427 are based on the chemical scaffold of PF-06767832.

Figure 5. Chemical structures of M1-mAChR allosteric ligands developed by Vanderbilt University

VU0453595 and VU6004256 are based on the chemical scaffold of VU0486846.

Figure 6. Ligand-induced signalling bias at the M1-mAChR

(A) ACh binds to the orthosteric pocket of the M1-mAChR to activate the receptor, resulting in induction of conformational changes within the receptor. This leads to coupling of the receptor to G proteins and β-arrestin with equivalent potencies, and subsequent activation of multiple signalling pathways downstream of G proteins and β-arrestin. (B) Binding of an ‘unbiased’ PAM-agonist to the M1-mAChR allosteric pocket potentiates coupling to G proteins and β-arrestin with equivalent potencies, but results in enhanced activation of multiple signalling pathways downstream of G proteins and β-arrestin. (C) Pilocarpine is biased towards G protein signalling over β-arrestin signalling, hence binding to the orthosteric pocket of the M1-mAChR results in receptor conformations that promote coupling to G proteins with greater potency than to β-arrestin. This results in activation of signalling pathways downstream of G proteins over β-arrestin.

Figure 7. Linking M1-mAChR drug development to pathological stages of AD

In the early stages of the disease when there is gradual loss of cholinergic neurons and modest depletion of ACh as well as MCI, use of ‘pure’ M1-PAMs may be a good strategy to potentiate the actions of ACh and improve cognitive function with minimal risk of adverse effects. With progression to the moderate stages of the disease, there is relatively increased loss of ACh coupled with more pronounced disruptions to cognitive and behavioural functions. At this stage, the use M1-mAChR PAM-agonists to simultaneously potentiate the actions of ACh and directly activate the receptors may be an ideal strategy. In the severe stages of AD, there is significant depletion of ACh and severe loss of cognitive function. Orthosteric or bitopic ligands could be ideal in ‘replacing’ the actions of the depleted ACh to improve cognitive function. In developing these strategies, it is important to assess the risk-benefit profile of these ligands in the context of the patient.