Muscarinic acetylcholine receptors as CNS drug targets

Langmead, Christopher J.; Watson, Jeannette M.; Reavill, Charlie

doi:10.1016/j.pharmthera.2007.09.009

Cited by 380 publications

(411 citation statements)

References 99 publications

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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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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

View full text Add to dashboard Cite

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“…Targeting the M 1 mAChR has proved promising; the M 1 /M 4 mAChR-preferring agonist, xanomeline, improved cognitive behaviors in both Alzheimer and schizophrenic patients (1,2). However, like all mAChR-based therapeutics, xanomeline targets the ACh (orthosteric) binding site, which is highly conserved across the mAChR family (3). As such, the effectiveness of xanomeline is limited by inadequate subtype selectivity and adverse effects via peripheral M 2 and M 3 mAChRs (1,2).…”

mentioning

confidence: 99%

Molecular Mechanisms of Bitopic Ligand Engagement with the M1 Muscarinic Acetylcholine Receptor

Keov

López

Devine

et al. 2014

Journal of Biological Chemistry

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Background: Bitopic ligands bind concomitantly to orthosteric and allosteric receptor sites. Results: Residues affecting binding and biased signaling of the selective agonists TBPB and 77-LH-28-1 were identified at the M 1 muscarinic receptor. Conclusion: Novel bitopic ligand binding poses and mechanisms of receptor activation were identified. Significance: Understanding the basis of bitopic ligand mechanisms can enable the design of selective ligands.

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“…2 mAChRs are widely expressed throughout the body with varying degrees of expression at a particular target organ or synapse. 2 Consequently, mAChRs regulate an extensive array of signaling pathways and biological responses including cognition, attention, cardiovascular function, secretory, and GI function. 3 The M 1 receptor has been viewed as an attractive therapeutic target and modulation of this subtype may provide a novel treatment strategy for a variety of disorders of the CNS.…”

mentioning

confidence: 99%

Chemical Modification of the M₁ Agonist VU0364572 Reveals Molecular Switches in Pharmacology and a Bitopic Binding Mode

Digby

Utley

Lamsal

et al. 2012

ACS Chem. Neurosci.

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ABSTRACT:We previously reported the discovery of VU0364572 and VU0357017 as M 1 -selective agonists that appear to activate M 1 through actions at an allosteric site. Previous studies have revealed that chemical scaffolds for many allosteric modulators contain molecular switches that allow discovery of allosteric antagonists and allosteric agonists or positive allosteric modulators (PAMs) based on a single chemical scaffold. Based on this, we initiated a series of studies to develop selective M 1 allosteric antagonists based on the VU0364572 scaffold. Interestingly, two lead antagonists identified in this series, VU0409774 and VU0409775, inhibited ACh-induced Ca 2+ responses at rat M 1−5 receptor subtypes, suggesting they are nonselective muscarinic antagonists. VU0409774 and VU0409775 also completely displaced binding of the nonselective radioligand [3 H]-NMS at M 1 and M 3 mAChRs with affinities similar to their functional IC 50 values. Finally, Schild analysis revealed that these compounds inhibit M 1 responses through a fully competitive interaction at the orthosteric binding site. This surprising finding prompted further studies to determine whether agonist activity of VU0364572 and VU0357017 may also engage in previously unappreciated actions at the orthosteric site on M 1 . Surprisingly, both VU0364572 and VU0357017 completely displaced [ 3 H]-NMS binding to the orthosteric site of M 1 −M 5 receptors at high concentrations. Furthermore, evaluation of agonist activity in systems with varying levels of receptor reserve and Furchgott analysis using a cell line expressing M 1 under control of an inducible promotor was consistent with an action of these compounds as weak orthosteric partial agonists of M 1 . However, consistent with previous studies suggesting actions at a site that is distinct from the orthosteric binding site, VU0364572 or VU0357017 slowed the rate of [ 3 H]-NMS dissociation from CHOrM 1 membranes. Together, these results suggest that VU0364572 and VU0357017 act as bitopic ligands and that novel antagonists in this series act as competitive orthosteric site antagonists.

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Muscarinic acetylcholine receptors as CNS drug targets

Cited by 380 publications

References 99 publications

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

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

Molecular Mechanisms of Bitopic Ligand Engagement with the M1 Muscarinic Acetylcholine Receptor

Chemical Modification of the M₁ Agonist VU0364572 Reveals Molecular Switches in Pharmacology and a Bitopic Binding Mode

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Muscarinic acetylcholine receptors as CNS drug targets

Cited by 380 publications

References 99 publications

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

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

Molecular Mechanisms of Bitopic Ligand Engagement with the M1 Muscarinic Acetylcholine Receptor

Chemical Modification of the M1 Agonist VU0364572 Reveals Molecular Switches in Pharmacology and a Bitopic Binding Mode

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Product

Resources

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Chemical Modification of the M₁ Agonist VU0364572 Reveals Molecular Switches in Pharmacology and a Bitopic Binding Mode