M1 Muscarinic Agonists Target Major Hallmarks of Alzheimer’s Disease – The Pivotal Role of Brain M1 Receptors

Fisher, Abraham

doi:10.1159/000113712

Cited by 71 publications

(71 citation statements)

References 42 publications

(35 reference statements)

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“…Two widely acknowledged pathophysiological hallmarks of AD are the accumulation of β-amyloid plaques and the formation of neurofibrillary tangles as a result of tau-protein hyperphosphorylation, 5 "vicious cycles" that both lead to substantive CNS cholinergic neural death in the cortical and hippocampal regions of the basal forebrain (flowchart depicted in Figure 3). …”

Section: ■ the Cholinergic Hypothesis Of Memory Dysfunctionmentioning

confidence: 99%

Development of M₁ mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits

Davie

Christopoulos

Scammells

2013

ACS Chem. Neurosci.

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Since the cholinergic hypothesis of memory dysfunction was first reported, extensive research efforts have focused on elucidating the mechanisms by which this intricate system contributes to the regulation of processes such as learning, memory, and higher executive function. Several cholinergic therapeutic targets for the treatment of cognitive deficits, psychotic symptoms, and the underlying pathophysiology of neurodegenerative disorders, such as Alzheimer's disease and schizophrenia, have since emerged. Clinically approved drugs now exist for some of these targets; however, they all may be considered suboptimal therapeutics in that they produce undesirable off-target activity leading to side effects, fail to address the wide variety of symptoms and underlying pathophysiology that characterize these disorders, and/or afford little to no therapeutic effect in subsets of patient populations. A promising target for which there are presently no approved therapies is the M 1 muscarinic acetylcholine receptor (M 1 mAChR). Despite avid investigation, development of agents that selectively activate this receptor via the orthosteric site has been hampered by the high sequence homology of the binding site between the five muscarinic receptor subtypes and the wide distribution of this receptor family in both the central nervous system (CNS) and the periphery. Hence, a plethora of ligands targeting less structurally conserved allosteric sites of the M 1 mAChR have been investigated. This Review aims to explain the rationale behind allosterically targeting the M 1 mAChR, comprehensively summarize and critically evaluate the M 1 mAChR allosteric ligand literature to date, highlight the challenges inherent in allosteric ligand investigation that are impeding their clinical advancement, and discuss potential methods for resolving these issues. KEYWORDS: M 1 mAChR, allosteric ligands, Alzheimer's disease, schizophrenia, cognitive deficits, memory T he muscarinic acetylcholine receptor (mAChR) family is a group of rhodopsin-like (Family A) G protein-coupled receptors (GPCRs) consisting of five distinct subtypes M 1 −M 5 . Activation of the M 1 , M 3 , and M 5 receptor subtypes primarily results in coupling to the G q/11 family of G proteins, activation of phospholipase C (PLC), release of inositol-1,4,5-trisphosphate (IP 3 ), and subsequent mobilization of intracellular calcium Ca 2+ . Activation of the M 2 and M 4 receptor subtypes primarily results in coupling to the G i/o family of G proteins, inhibition of adenylate cyclase (AC), reduction in cyclic AMP (cAMP), and a decrease in neurotransmitter release via the blockage of voltage-gated calcium channels (Figure 1). These pathways represent a generalized view of each receptor's coupling capacity, as all five subtypes couple to a broader range of G protein-and non-G protein-mediated signaling and regulatory pathways, 1 ultimately leading to the regulation of enzymes and neurotransmitters critical for intercellular chemical communication and biological function. In a ...

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Section: ■ the Cholinergic Hypothesis Of Memory Dysfunctionmentioning

confidence: 99%

Development of M₁ mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits

Davie

Christopoulos

Scammells

2013

ACS Chem. Neurosci.

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“…M1, M3, and M5 couple to Gq and activate phospholipase C, whereas M2 and M4 couple to Gi/o and related ion channels and adenylyl cyclase. There is strong evidence that the main autonomic adverse effects of cholinergic drugs are mediated by the activation of peripheral M2 and M3 receptors, while cognitive effects may be related to M1 receptor activation (Anagnostaras et al, 2003;Bymaster et al, 2003a, b, c;Hasselmo, 2006;Fisher, 2008;Langmead et al, 2008;Conn et al, 2009a). Given this evidence, drugs acting specifically at M4 or M5 receptors may have fewer side effects than the current non-specific drugs.…”

Section: Non-dopaminergic Therapiesmentioning

confidence: 99%

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

Smith

Wichmann

Factor

et al. 2011

Neuropsychopharmacol

194

137

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The demonstration that dopamine loss is the key pathological feature of Parkinson's disease (PD), and the subsequent introduction of levodopa have revolutionalized the field of PD therapeutics. This review will discuss the significant progress that has been made in the development of new pharmacological and surgical tools to treat PD motor symptoms since this major breakthrough in the 1960s. However, we will also highlight some of the challenges the field of PD therapeutics has been struggling with during the past decades. The lack of neuroprotective therapies and the limited treatment strategies for the nonmotor symptoms of the disease (ie, cognitive impairments, autonomic dysfunctions, psychiatric disorders, etc.) are among the most pressing issues to be addressed in the years to come. It appears that the combination of early PD nonmotor symptoms with imaging of the nigrostriatal dopaminergic system offers a promising path toward the identification of PD biomarkers, which, once characterized, will set the stage for efficient use of neuroprotective agents that could slow down and alter the course of the disease.

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“…Muscarinic receptor activation has been shown to reverse cognitive and behavioral deficits in animal models of schizophrenia and Alzheimer's disease, and the M 1 receptor specifically has been implicated in mediating these effects (Jones et al, 2005;dx.doi.org/10.1124/jpet.115.226910. s This article has supplemental material available at jpet.aspetjournals.org. Langmead et al, 2008;Barak and Weiner 2011;Fisher 2008). The most direct evidence for the utility of M 1 activators in treating schizophrenia and Alzheimer's disease comes from clinical trials using xanomeline, a muscarinic partial agonist with modest selectivity for M 1 and M 4 receptors.…”

Section: Introductionmentioning

confidence: 99%

Evidence for Classical Cholinergic Toxicity Associated with Selective Activation of M1 Muscarinic Receptors

Alt

Pendri

Bertekap

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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The muscarinic acetylcholine receptor subtype 1 (M 1 ) receptors play an important role in cognition and memory, and are considered to be attractive targets for the development of novel medications to treat cognitive impairments seen in schizophrenia and Alzheimer's disease. Indeed, the M 1 agonist xanomeline has been shown to produce beneficial cognitive effects in both Alzheimer's disease and schizophrenia patients. Unfortunately, the therapeutic utility of xanomeline was limited by cholinergic side effects (sweating, salivation, gastrointestinal distress), which are believed to result from nonselective activation of other muscarinic receptor subtypes such as M 2 and M 3 . Therefore, drug discovery efforts targeting the M 1 receptor have focused on the discovery of compounds with improved selectivity profiles. Recently, allosteric M 1 receptor ligands have been described, which exhibit excellent selectivity for M 1 over other muscarinic receptor subtypes. In the current study, the following three compounds with mixed agonist/positive allosteric modulator activities that are highly functionally selective for the M 1 receptor were tested in rats, dogs, and cynomologous monkeys: (3-((1S,2S)-2-hydrocyclohexyl)-6-((6-(1-methyl-1H-pyrazol-4-yl) pyridin-3-yl)methyl)benzo[h]quinazolin-4(3H)-one; 1-((4-cyano-4-(pyridin-2-yl)piperidin-1-yl)methyl)-4-oxo-4H-quinolizine-3-carboxylic acid; and (R)-ethyl 3-(2-methylbenzamido)-[1, 49-bipiperidine]-19-carboxylate). Despite their selectivity for the M 1 receptor, all three compounds elicited cholinergic side effects such as salivation, diarrhea, and emesis. These effects could not be explained by activity at other muscarinic receptor subtypes, or by activity at other receptors tested. Together, these results suggest that activation of M 1 receptors alone is sufficient to produce unwanted cholinergic side effects such as those seen with xanomeline. This has important implications for the development of M 1 receptor-targeted therapeutics since it suggests that dose-limiting cholinergic side effects still reside in M 1 receptor selective activators.

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M1 Muscarinic Agonists Target Major Hallmarks of Alzheimer’s Disease – The Pivotal Role of Brain M1 Receptors

Cited by 71 publications

References 42 publications

Development of M₁ mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits

Development of M₁ mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

Evidence for Classical Cholinergic Toxicity Associated with Selective Activation of M1 Muscarinic Receptors

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M1 Muscarinic Agonists Target Major Hallmarks of Alzheimer’s Disease – The Pivotal Role of Brain M1 Receptors

Cited by 71 publications

References 42 publications

Development of M1 mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits

Development of M1 mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

Evidence for Classical Cholinergic Toxicity Associated with Selective Activation of M1 Muscarinic Receptors

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Product

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Development of M₁ mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits

Development of M₁ mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits