Muscarinic Receptor Agonists and Antagonists in the Treatment of Alzheimers Disease

Clader, John W.; Wang, Yuguang

doi:10.2174/138161205774370762

Cited by 102 publications

(91 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…60 This enhanced release of ACh, by activating postsynaptic M1 mAChR, can lead to improvement in cognitive processing, because M2 mAChR-knockout mice do not mediate cognition and memory, whereas M1 mAChRs are clearly involved in such processes. 47,61,62 An additional advantage of M2 antagonists is that by elevating synaptic ACh, these will also activate both postsynaptic mAChR, as well as nicotinic receptors. This would distinguish the M2 antagonists from M1 agonists, and serves to make this treatment approach more like AChE-Is at the level of the synapse.…”

Section: M2 Muscarinic Antagonistsmentioning

confidence: 99%

Cholinergic Treatments with Emphasis on M1 Muscarinic Agonists as Potential Disease-Modifying Agents for Alzheimer's Disease

2008

View full text Add to dashboard Cite

Summary:The only prescribed drugs for treatment of Alzheimer's disease (AD) are acetylcholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine, and tacrine) and memantine, an NMDA antagonist. These drugs ameliorate mainly the symptoms of AD, such as cognitive impairments, rather than halting or preventing the causal neuropathology. There is currently no cure for AD and there is no way to stop its progression, yet there are numerous therapeutic approaches directed against various pathological hallmarks of AD that are extensively being pursued. In this context, the three major hallmark characteristics of AD (i.e., the CNS cholinergic hypofunction, formation of ␤-amyloid plaques, and tangles containing hyperphosphorylated tau proteins) are apparently linked. Such linkages may have therapeutic implications, and this review is an attempt to analyze these versus the advantages and drawbacks of some cholinergic compounds, such as acetylcholinesterase inhibitors, M1 muscarinic agonists, M2 antagonists, and nicotinic agonists. Among the reviewed treatments, M1 selective agonists emerge, in particular, as potential disease modifiers.

show abstract

Section: M2 Muscarinic Antagonistsmentioning

confidence: 99%

Cholinergic Treatments with Emphasis on M1 Muscarinic Agonists as Potential Disease-Modifying Agents for Alzheimer's Disease

2008

View full text Add to dashboard Cite

show abstract

“…4,5 The reduction of cholinergic neurons in the basal nuclear complex is associated with the cognitive deficits observed in patients with Alzheimer's disease. 6,7 A link between mAChR function and disease pathology has been suggested, with the M 1 mAChR subtype particularly highlighted for a role in cognition. 7,8 Acetylcholinesterase inhibitors are currently used to treat the cognitive deficits associated with…”

mentioning

confidence: 99%

“…It is likely that such side-effects are due activation of M 2 and M 3 mAChRs expressed in the periphery. 7 Accordingly, there has been considerable focus upon the design of ligands that selectively activate the M 1 mAChR. However, the design of selective orthosteric agonists for the M 1 mAChR has proven difficult, due to the highly conserved orthosteric pocket of all the mAChRs (M 1 -M 5 ).…”

mentioning

confidence: 99%

Novel Fused Arylpyrimidinone Based Allosteric Modulators of the M₁ Muscarinic Acetylcholine Receptor

Mistry

Lim

Jörg

et al. 2016

ACS Chem. Neurosci.

View full text Add to dashboard Cite

. (2016) Novel fused arylpyrimidinone based allosteric modulators of the M1 muscarinic acetylcholine receptor. ACS Chemical Neuroscience, 7 (5). pp. 647-661. ISSN 1948-7193 Access from the University of Nottingham repository: http://eprints.nottingham.ac.uk/31897/1/acschemneuro%252E6b00018.pdf Copyright and reuse:The Nottingham ePrints service makes this work by researchers of the University of Nottingham available open access under the following conditions. This article is made available under the Creative Commons Attribution Non-commercial licence and may be reused according to the conditions of the licence. For more details see: http://creativecommons.org/licenses/by-nc/2.5/ A note on versions:The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the repository url above for details on accessing the published version and note that access may require a subscription.For more information, please contact eprints@nottingham.ac.uk Just Accepted "Just Accepted" manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides "Just Accepted" as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. "Just Accepted" manuscripts appear in full in PDF format accompanied by an HTML abstract. "Just Accepted" manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). "Just Accepted" is an optional service offered to authors. Therefore, the "Just Accepted" Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the "Just Accepted" Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these "Just Accepted" manuscripts. ABSTRACT: Benzoquinazolinone 1 is a positive allosteric modulator (PAM) of the M 1 muscarinic acetylcholine receptor (mAChR), which is significantly more potent than the prototypical PAM, 1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (BQCA). In this study, we explored the structural determinants that underlie the activity of 1 as a PAM of the M 1 mAChR.We paid particular attention to the importance of the tricyclic scaffold of compound 1, for the activity of the molecule. Complete deletion of the peripheral fused benzene ring caused a significant decrease in affinity and binding cooperativity with acetylcholine (ACh). ...

show abstract

“…Cholinesterase inhibitors were the first generation of such candidate therapeutics (11)(12)(13)(14)(15). A second generation of candidate therapeutics has included a series of attempts to inhibit the formation of amyloid plaques.…”

mentioning

confidence: 99%

Small molecule blockers of the Alzheimer Aβ calcium channel potently protect neurons from Aβ cytotoxicity

Díaz

Šimáková

Jacobson

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

107

View full text Add to dashboard Cite

Alzheimer's disease (AD) is a common, chronic neurodegenerative disease that is thought to be caused by the neurotoxic effect of the Amyloid beta peptides (A␤). We have hypothesized that the intrinsic A␤ calcium channel activity of the oligomeric A␤ polymer may be responsible for the neurotoxic properties of A␤, and that A␤ channel blockers may be candidate AD therapeutics. As a consequence of a rational search paradigm based on the model structure of the A␤ channel, we have identified two compounds of interest: MRS2481 and an enatiomeric species, MRS2485. These are amphiphilic pyridinium salts that both potently block the A␤ channel and protect neurons from A␤ toxicity. Both block the A␤ channel with similar potency (Ϸ500 nM) and efficacy (100%). However, we find that inhibition by MRS2481 is easily reversible, whereas inhibition by MRS2485 is virtually irreversible. We suggest that both species deserve consideration as candidates for Alzheimer's disease drug discovery.brain ͉ neurodegeneration ͉ rational drug design ͉ drug ͉ toxicity A lzheimer's disease (AD) is a chronic neurodegenerative disease characterized behaviorally by progressive memory loss, and neuronal degeneration in the cerebral cortex, hippocampus, and elsewhere (1, 2). The neuropathology of AD is characterized by amyloid plaques and neuro-fibrillary tangles. The amyloid plaque material has been found to be composed principally of a 40Ϫ42-residue peptide, called amyloid ␤-peptide, or ''A␤'' (3). Both forms of A␤40/42 have been found to be kill neurons and certain other cells in culture. Altogether, these findings have provided strong support for the hypothesis that AD is due to neurotoxic effects of A␤ on susceptible neurons (4-10).The mechanism of A␤ neurotoxicity has been pursued for decades in hopes of translating such knowledge into a pharmaceutical therapy for AD. Cholinesterase inhibitors were the first generation of such candidate therapeutics (11-15). A second generation of candidate therapeutics has included a series of attempts to inhibit the formation of amyloid plaques. Active (16-23) and passive (24) immunization approaches are presently being tested. However, some patients in the active human immunization trials have developed meningoencephalitis (25,26). Yet another alternative has been to reduce the levels of A␤ in the brain by inhibiting the proteolytic enzymes associated with trimming APP into A␤ 40 or 42 (27-31).An entirely different approach to the mechanism of A␤ neurotoxicity has been developed following the observation that oligomers of A␤ peptides themselves formed calcium conducting channels in bilayer membranes in vitro (32)(33)(34)(35), and in intact neurons (36). The target of the A␤ peptide in biological and model membranes is phosphatidylserine (PS), the proapoptic signaling phospholipid (37). Subsequently the calcium channel properties of A␤ have been verified in many other laboratories (38-42). We and others have therefore hypothesized that calcium conducted into the target neurons by the A␤ channel might be respo...

show abstract

Muscarinic Receptor Agonists and Antagonists in the Treatment of Alzheimers Disease

Cited by 102 publications

References 31 publications

Cholinergic Treatments with Emphasis on M1 Muscarinic Agonists as Potential Disease-Modifying Agents for Alzheimer's Disease

Cholinergic Treatments with Emphasis on M1 Muscarinic Agonists as Potential Disease-Modifying Agents for Alzheimer's Disease

Novel Fused Arylpyrimidinone Based Allosteric Modulators of the M₁ Muscarinic Acetylcholine Receptor

Small molecule blockers of the Alzheimer Aβ calcium channel potently protect neurons from Aβ cytotoxicity

Contact Info

Product

Resources

About

Muscarinic Receptor Agonists and Antagonists in the Treatment of Alzheimers Disease

Cited by 102 publications

References 31 publications

Cholinergic Treatments with Emphasis on M1 Muscarinic Agonists as Potential Disease-Modifying Agents for Alzheimer's Disease

Cholinergic Treatments with Emphasis on M1 Muscarinic Agonists as Potential Disease-Modifying Agents for Alzheimer's Disease

Novel Fused Arylpyrimidinone Based Allosteric Modulators of the M1 Muscarinic Acetylcholine Receptor

Small molecule blockers of the Alzheimer Aβ calcium channel potently protect neurons from Aβ cytotoxicity

Contact Info

Product

Resources

About

Novel Fused Arylpyrimidinone Based Allosteric Modulators of the M₁ Muscarinic Acetylcholine Receptor