Abstract
This article describes the discovery and development of the first highly selective, small molecule antagonist of the muscarinic acetylcholine receptor subtype I (mAChR1 or M1). An M1 functional, cell-based, calcium-mobilization assay identified three distinct chemical series with initial selectivity for M1 versus M4. An iterative parallel synthesis approach was employed to optimize all three series in parallel, which led to the development of novel microwave-assisted chemistry and provided important take home lessons for probe development projects. Ultimately, this effort produced VU0255035, a potent (IC50 = 130 nM) and selective ( > 75-fold vs. M2-M5 and > 10 iM vs. a panel of 75 GPCRs, ion channels and transporters) small molecule M1 antagonist. Further profiling demonstrated that VU0255035 was centrally penetrant (BrainAUC/PlasmaAUC of 0.48) and active in vivo, rendering it acceptable as both an in vitro and in vivo MLSCN/ MLPCN probe molecule for studying and dissecting M1 function.
Keywords: Muscarinic, acetylcholine, mAChR, M1, antagonist
Current Topics in Medicinal Chemistry
Title: Discovery and Development of a Potent and Highly Selective Small Molecule Muscarinic Acetylcholine Receptor Subtype I (mAChR 1 or M1) Antagonist In Vitro and In Vivo Probe
Volume: 9 Issue: 13
Author(s): Satyawan Jadhav, Craig W. Lindsley, P. Jeffrey Conn, Fang Zheng, Matthew M. Mock, Colleen M. Niswender, Joy Marlo, Carrie K. Jones, Leslie A. Aldrich, C. David Weaver, Matthew M. Mulder, J. Phillip Kennedy, Natalia T. Nalywajko, Richard Williams, Thomas M. Bridges, L. Michelle Lewis and Douglas J. Sheffler
Affiliation:
Keywords: Muscarinic, acetylcholine, mAChR, M1, antagonist
Abstract: This article describes the discovery and development of the first highly selective, small molecule antagonist of the muscarinic acetylcholine receptor subtype I (mAChR1 or M1). An M1 functional, cell-based, calcium-mobilization assay identified three distinct chemical series with initial selectivity for M1 versus M4. An iterative parallel synthesis approach was employed to optimize all three series in parallel, which led to the development of novel microwave-assisted chemistry and provided important take home lessons for probe development projects. Ultimately, this effort produced VU0255035, a potent (IC50 = 130 nM) and selective ( > 75-fold vs. M2-M5 and > 10 iM vs. a panel of 75 GPCRs, ion channels and transporters) small molecule M1 antagonist. Further profiling demonstrated that VU0255035 was centrally penetrant (BrainAUC/PlasmaAUC of 0.48) and active in vivo, rendering it acceptable as both an in vitro and in vivo MLSCN/ MLPCN probe molecule for studying and dissecting M1 function.
Export Options
About this article
Cite this article as:
Jadhav Satyawan, Lindsley W. Craig, Conn Jeffrey P., Zheng Fang, Mock M. Matthew, Niswender M. Colleen, Marlo Joy, Jones K. Carrie, Aldrich A. Leslie, Weaver David C., Mulder M. Matthew, Kennedy Phillip J., Nalywajko T. Natalia, Williams Richard, Bridges M. Thomas, Lewis Michelle L. and Sheffler J. Douglas, Discovery and Development of a Potent and Highly Selective Small Molecule Muscarinic Acetylcholine Receptor Subtype I (mAChR 1 or M1) Antagonist In Vitro and In Vivo Probe, Current Topics in Medicinal Chemistry 2009; 9 (13) . https://dx.doi.org/10.2174/156802609789753635
DOI https://dx.doi.org/10.2174/156802609789753635 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
- 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
-
3D-QSAR Studies on Plasmodium falciparam Proteins: A Mini-Review
Combinatorial Chemistry & High Throughput Screening Cancer Stem Cells: A New Paradigm for Understanding Tumor Growth and Progression and Drug Resistance
Current Medicinal Chemistry Psychiatric Rehabilitation Pertaining to Health Care Environments: Facilitating Skills and Supports of People with Mental Illness in Relation to their Mental and Physical Health Care
Current Psychiatry Reviews Structure Function Analysis of West Nile Virus RNA Dependent RNA Polymerase: Molecular Model and Implications for Drug Design
Medicinal Chemistry Key Targets and Relevant Inhibitors for the Drug Discovery of Tuberculosis
Current Drug Targets Synthesis and Pharmacological Screening of Novel 1,3-Disubstituted 5-Pyrazolones as Anticonvulsant Agents
Current Bioactive Compounds QSAR-Derived Choline Kinase Inhibitors: How Rational can Antiproliferative Drug Design Be?
Current Medicinal Chemistry Role of Potential COVID-19 Immune System Associated Genes and the Potential Pathways Linkage with Type-2 Diabetes
Combinatorial Chemistry & High Throughput Screening Characterization of Rhodamine Conjugated Agiotensin II Peptide: Synthesis, Analysis and Receptor Binding and Internalization.
Protein & Peptide Letters Targeting Complement in Rheumatoid Arthritis
Current Rheumatology Reviews Effective Chemicals against Novel Coronavirus (COVID-19) in China
Current Topics in Medicinal Chemistry Design and Synthesis of a (N-Alkylaminoalkyl-Substituted)Arylalkenylamide Drug Discovery Library
Letters in Drug Design & Discovery New Insights into the Regulation of Liver Inflammation and Oxidative Stress
Mini-Reviews in Medicinal Chemistry Pharmacological Strategies for Inhibition of Thrombin Activity
Current Pharmaceutical Design Microwave Assisted Synthesis, Biological Characterization and Docking Studies of Pyrimidine Derivatives
Current Microwave Chemistry Targeted Tumor Immunotherapy: Are Vaccines the Future of Cancer Treatment?
Current Drug Therapy Viral Gastroenteritis in Adults
Recent Patents on Anti-Infective Drug Discovery Drug Discovery in Enteroviral Infections
Infectious Disorders - Drug Targets The Lung Disease of Rheumatoid Arthritis
Current Respiratory Medicine Reviews Synthetic Glycosides and Glycoconjugates of Low Molecular Weight Natural Products
Current Pharmaceutical Design