Abstract
There is mounting evidence from preclinical and early proof-of-concept studies suggesting that selective modulation of the M1 muscarinic receptor is efficacious in cognitive models of Alzheimer's disease (AD). A number of nonselective M1 muscarinic agonists have previously shown positive effects on cognitive function in AD patients, but were limited due to cholinergic adverse events thought to be mediated by pan activation of the M2 to M5 sub-types. Thus, there is a need to identify selective activators of the M1 receptor to evaluate their potential in cognitive disorders. One strategy to confer selectivity for M1 is the identification of allosteric agonists or positive allosteric modulators, which would target an allosteric site on the M1 receptor rather than the highly conserved orthosteric acetylcholine binding site. BQCA has been identified as a highly selective carboxylic acid M1 PAM and this review focuses on an extensive lead optimization campaign undertaken on this compound.
Keywords: Allosteric, Alzheimer's, BQCA, modulator, muscarinic, positive, quinolone.
Graphical Abstract
Current Topics in Medicinal Chemistry
Title:SAR Studies on Carboxylic Acid Series M1 Selective Positive Allosteric Modulators (PAMs)
Volume: 14 Issue: 15
Author(s): Scott D. Kuduk and Douglas C. Beshore
Affiliation:
Keywords: Allosteric, Alzheimer's, BQCA, modulator, muscarinic, positive, quinolone.
Abstract: There is mounting evidence from preclinical and early proof-of-concept studies suggesting that selective modulation of the M1 muscarinic receptor is efficacious in cognitive models of Alzheimer's disease (AD). A number of nonselective M1 muscarinic agonists have previously shown positive effects on cognitive function in AD patients, but were limited due to cholinergic adverse events thought to be mediated by pan activation of the M2 to M5 sub-types. Thus, there is a need to identify selective activators of the M1 receptor to evaluate their potential in cognitive disorders. One strategy to confer selectivity for M1 is the identification of allosteric agonists or positive allosteric modulators, which would target an allosteric site on the M1 receptor rather than the highly conserved orthosteric acetylcholine binding site. BQCA has been identified as a highly selective carboxylic acid M1 PAM and this review focuses on an extensive lead optimization campaign undertaken on this compound.
Export Options
About this article
Cite this article as:
Kuduk D. Scott and Beshore C. Douglas, SAR Studies on Carboxylic Acid Series M1 Selective Positive Allosteric Modulators (PAMs), Current Topics in Medicinal Chemistry 2014; 14 (15) . https://dx.doi.org/10.2174/1568026614666140826120224
DOI https://dx.doi.org/10.2174/1568026614666140826120224 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Medicinal Chemistry Advancement in Life-Threatening Diseases
The current issue will highlight concise reports that specify ground-breaking insights, including the novel discovery of drug targets and their action mechanism or drugs of novel classes. These are projected to encourage medicinal chemistry future efforts to address the most challenging medical needs. The current issue highlights further efforts to ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Perispinal Etanercept for Treatment of Alzheimers Disease
Current Alzheimer Research The Hidden Impact of COVID-19 on Sexual and Reproductive Health and Rights of Women in India
Current Women`s Health Reviews The Application of Mass Spectrometry to Proteomics and Metabolomics in Biomarker Discovery and Drug Development
Current Molecular Pharmacology Acknowledgements to Reviewers:
Current Alzheimer Research Therapeutic Approaches Targeting Pathological Tau Aggregates
Current Pharmaceutical Design The Neurovascular Protection Afforded by Delayed Local Hypothermia after Transient Middle Cerebral Artery Occlusion
Current Neurovascular Research Spatio-temporal Distribution of Meningitis in HIV Patients in Northern Egypt (2000-2018)
Current HIV Research Meet Our Editorial Board Member:
Central Nervous System Agents in Medicinal Chemistry Conditioned Avoidance Response in the Development of New Antipsychotics
Current Pharmaceutical Design Sodium Oxybate Therapy for Alcohol Withdrawal Syndrome and Keeping of Alcohol Abstinence
Current Drug Metabolism The Role of Apoptotic Pathways in Alzheimers Disease Neurodegeneration and Cell Death
Current Alzheimer Research Patent Selections:
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery (Discontinued) Brain Oxidative Markers in Stress: Possible New Drug Targets Against Neuroinflammation
Current Neuropharmacology Novel Aspects of Natural and Modified Vinca Alkaloids
Current Medicinal Chemistry - Anti-Cancer Agents Pharmacotherapy of Borderline Personality Disorder: A Systematic Review
Current Medicinal Chemistry Resolution-Associated Molecular Patterns (RAMPs) as Endogenous Regulators of Glia Functions in Neuroinflammatory Disease
CNS & Neurological Disorders - Drug Targets A Common Biological Mechanism in Cancer and Alzheimers Disease?
Current Alzheimer Research Impact on DNA Methylation in Cancer Prevention and Therapy by Bioactive Dietary Components
Current Medicinal Chemistry Platelet-derived Growth Factor Receptor-beta is Differentially Regulated in Primary Mouse Pericytes and Brain Slices
Current Neurovascular Research Adipokines, Metabolism and the Immune Response in the Regulation of Inflammation
Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents