A New Era of Muscarinic Acetylcholine Receptor Modulators in Neurological Diseases, Cancer and Drug Abuse

Abstract

The cholinergic pathways in the central nervous system (CNS) play a pivotal role in different cognitive functions of the brain, such as memory and learning. This review takes a dive into the pharmacological side of this important part of CNS function, taking into consideration muscarinic receptors and cholinesterase enzymes. Targeting a specific subtype of five primary muscarinic receptor subtypes (M1-M5) through agonism or antagonism may benefit patients; thus, there is a great pharmaceutical research interest. Inhibition of AChE and BChE, orthosteric or allosteric, or partial agonism of M1 mAChR are correlated with Alzheimer's disease (AD) symptoms improvement. Agonism or antagonism on different muscarinic receptor subunits may lessen schizophrenia symptoms (especially positive allosteric modulation of M4 mAChR). Selective antagonism of M4 mAChR is a promising treatment for Parkinson's disease and dystonia, and the adverse effects are limited compared to inhibition of all five mAChR. Additionally, selective M5 antagonism plays a role in drug independence behavior. M3 mAChR overexpression is associated with malignancies, and M3R antagonists seem to have a therapeutic potential in cancer, while M1R and M2R inhibition leads to reduction of neoangiogenesis. Depending on the type of cancer, agonism of mAChR may promote cancer cell proliferation (as M3R agonism does) or protection against further tumor development (M1R agonism). Thus, there is an intense need to discover new potent compounds with specific action on muscarinic receptor subtypes. Chemical structures, chemical modification of function groups aiming at action enhancement, reduction of adverse effects, and optimization of Drug Metabolism and Pharmacokinetics (DMPK) will be further discussed, as well as protein-ligand docking.

Keywords: Alzheimer’s disease; CNS; cancer; cholinergic system; drug abuse; muscarinic receptors; schizophrenia.

Figure 1

Muscarinic receptors signaling pathways, from [18].

Figure 2

Muscarinic receptors’ stimulatory and inhibitory actions, from [19].

Figure 3

Difference in residue existing in EL2 between M2 and the other subtypes, from [19].

Figure 4

Presence of glutamine in the middle of EL2 in M5 receptor, from [22].

Figure 5

Acetylcholine neurotransmission, from [25].

Figure 6

Mechanism of action of AChEIs. (A). Acetylcholine synthesis in nerve terminals from acetyl coenzyme A (acetyl CoA) and choline, in a reaction catalyzed by choline acetyltransferase (CAT). (B). Ca⁺² get into the cell during a synapse. (C). ACh is released from the vesicles and into the synaptic cleft. (D). ACh binds to receptors on the postsynaptic neuron. (E). AChE concurrently breaks down ACh. As a result, less information is transmitted since less ACh binds to receptors. Today, AChE inhibitors are utilized as medicine to address this problem, from [25].

Figure 7

Structural modifications of the initial hit molecule Compound 4 resulted in the invention of (S)-Compound 7 (HTL9936), from [34].

Figure 8

(A) Crystallization of interaction between M1-StaR-T4L and HTL9936, from [66]. (B) Binding location of M1-StaR-T4L, interaction with ligand HTL9936, from [34].

Figure 9

By blocking amyloidogenic cleavage via β-secretase1 (BACE1), activation of M1 mAChR with VU0486846 increases the non-amyloidogenic cleavage of amyloid precursor protein (APP) via ADAM10. This results in a decrease in the pathology caused by β-amyloid (Aβ) and supports the pro-cognitive function of VU0486846 in female AD mice, from [80].

Figure 10

In female APPswe mice, VU0486846 improves non-amyloidogenic processing of APP and reduces Aβ pathology. Images are representative of five independent experiments (scale bar, 500 μm), from [80].

Figure 11

Routes for M4 movement modulation, from [98].

Figure 12

N-carbethoxypiperidine is considered as a functional group (pharmacophore group) for M4 mAChR activation. In compound 7, N-carbethoxypiperidine was the substitute for the benzyl group in compound 6, from [42].

Figure 13

Cryo-electron microscopy (cryo-EM) structures for determining the 3D structure of biomacromolecules and complexes. (A). Cryo-EM map of VU154-Ipx. (B). Cryo-EM map of LY298-Ipx-, from [46].

Figure 14

VU154 and LY298 had stronger binding affinity to M4R with Ach instead of Ipx. Furthermore, LY298 is a more potent allosteric positive modulator than VU154, from [46].

Figure 15

(A). The essential amino acid residues and 3D crystal structures of M4 and M5 receptors. (B). Sequence alignment of M4/5. Residues with dark-blue color are identical in M4 and M5 receptors, and amino acids shown as light-blue color are indicated as similar, from [47].

Figure 16

Interactions between potent selective antagonists and key amino acids of the active insertion sites, from [47].

Figure 17

Efforts of SAR modulations of ML375, which led to ineffective analogs, from [48].

Figure 18

Molecular docking of molecule ML375 for M5 mAChR binding ability and pharmacological estimation, from [103]. The colors in the chart present the different M5-M2 mAChR chimeras used for prediction of potential allosteric sites within the transmembrane domain of M5 mAChR. This study highlights the ability of an allosteric modulator to target a different binding site of a highly conserved protein.

Figure 19

ACh released by cancel cells by membrane transporters (VAChT) functions as a ligand to many muscarinic receptor subtypes found in cancer cells. This agonism induces activation of many kinases and signaling pathways that modify the gene expression and enhance cancer cell proliferation, invasion, and metastasis. (A). The enzymes (choline acetyltransferase, ChAT) and transporters (vesicular acetylcholine transporter, VAChT) required for the production and release of ACh are expressed by neurons, immune cells, and cancer cells. In the extracellular space, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) quickly hydrolyze ACh to acetate and choline. (B). Muscarinic receptor (MR) subtypes that are expressed by nearby cancer cells are activated by ACh. Several protein kinases (like protein kinase C-α, PKC-α) and transcription factors (like extracellular signal-regulated protein kinase 1/2, ERK1/2) are activated by post-muscarinic receptor signaling, which changes the expression of genes encoding proteins that alter cell function and encourage cancer cell proliferation, survival, migration, invasion, and metastasis, from [108].

Figure 20

ACh activating M3 receptor, promoting ERa activity and cancer cell proliferation, from [105].