Abstract
Neuronal acetylcholine ion channel receptors (nAChRs), that exist in several subtypes resulting from a different organisation of various subunits around the central ion channel, are involved in a variety of functions and disorders of the central nervous system. There is evidence to implicate a deficit of nAChRs in the symptomatology of severe neurologic pathologies, such as Alzheimers and Parkinsons diseases. Reliable three-dimensional structures of nAChRs are not available yet, and this hampers adopting structure-based approaches in designing new ligands. Also pharmacophore models are not reliable enough to be used in ligand-based approaches to drug design and little structure-activity work has been reported so far. This paper deals with structure-activity relationships of a wide series of nicotinic ligands. It provides results from a study of the quantitative structure activity relationships (QSARs) based on literature data of about 270 nicotinic agonists, belonging to various chemical classes. The QSAR study was carried out by using either a classical Hansch approach or a Comparative Molecular Field Analysis (CoMFA). Within each congeneric series, Hansch-type equations revealed detrimental steric effects as the factors mainly modulating the receptor affinity, whereas CoMFA allowed us to merge progressively models obtained for each class of congeners into a more general one that showed good crossvalidation statistics. The CoMFA coefficient isocontour maps illustrated, at the 3-D level, the most relevant interactions responsible for a high receptor affinity, whereas the robustness of the global three-dimensional QSAR / CoMFA (n = 206, q2 = 0.749, r2 = 0.847, s= 0.600) model was supported by the high value of the prediction statistics (r2pred = 0.961) and confirmed by the satisfactory predictions of the affinity data of an external set of 18 recently published ligands with chemical structures even quite diverse from those included in the training set.
Keywords: Neuronal Nicotinic Acetylcholine Receptor (nAChR), Nicotine, Isonicotine, Arecolone, Isoarecolone, Anatoxin, Cytosine, Nicotine derivatives(N)
Current Medicinal Chemistry
Title: Ligands of Neuronal Nicotinic Acetylcholine Receptor (nAChR): Inferences from the Hansch and 3-D Quantitative Structure-Activity Relationship (QSAR) Models
Volume: 9 Issue: 1
Author(s): O. Nicolotti, M. Pellegrini-Calace, C. Altomare, A. Carotti, A. Carrieri and F. Sanz
Affiliation:
Keywords: Neuronal Nicotinic Acetylcholine Receptor (nAChR), Nicotine, Isonicotine, Arecolone, Isoarecolone, Anatoxin, Cytosine, Nicotine derivatives(N)
Abstract: Neuronal acetylcholine ion channel receptors (nAChRs), that exist in several subtypes resulting from a different organisation of various subunits around the central ion channel, are involved in a variety of functions and disorders of the central nervous system. There is evidence to implicate a deficit of nAChRs in the symptomatology of severe neurologic pathologies, such as Alzheimers and Parkinsons diseases. Reliable three-dimensional structures of nAChRs are not available yet, and this hampers adopting structure-based approaches in designing new ligands. Also pharmacophore models are not reliable enough to be used in ligand-based approaches to drug design and little structure-activity work has been reported so far. This paper deals with structure-activity relationships of a wide series of nicotinic ligands. It provides results from a study of the quantitative structure activity relationships (QSARs) based on literature data of about 270 nicotinic agonists, belonging to various chemical classes. The QSAR study was carried out by using either a classical Hansch approach or a Comparative Molecular Field Analysis (CoMFA). Within each congeneric series, Hansch-type equations revealed detrimental steric effects as the factors mainly modulating the receptor affinity, whereas CoMFA allowed us to merge progressively models obtained for each class of congeners into a more general one that showed good crossvalidation statistics. The CoMFA coefficient isocontour maps illustrated, at the 3-D level, the most relevant interactions responsible for a high receptor affinity, whereas the robustness of the global three-dimensional QSAR / CoMFA (n = 206, q2 = 0.749, r2 = 0.847, s= 0.600) model was supported by the high value of the prediction statistics (r2pred = 0.961) and confirmed by the satisfactory predictions of the affinity data of an external set of 18 recently published ligands with chemical structures even quite diverse from those included in the training set.
Export Options
About this article
Cite this article as:
Nicolotti O., Pellegrini-Calace M., Altomare C., Carotti A., Carrieri A. and Sanz F., Ligands of Neuronal Nicotinic Acetylcholine Receptor (nAChR): Inferences from the Hansch and 3-D Quantitative Structure-Activity Relationship (QSAR) Models, Current Medicinal Chemistry 2002; 9 (1) . https://dx.doi.org/10.2174/0929867023371463
DOI https://dx.doi.org/10.2174/0929867023371463 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...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
-
Increasing Delta-9-Tetrahydrocannabinol (Δ-9-THC) Content in Herbal Cannabis Over Time: Systematic Review and Meta-Analysis
Current Drug Abuse Reviews Non-IgE Mediated Food Allergy – Update of Recent Progress in Mucosal Immunity
Inflammation & Allergy - Drug Targets (Discontinued) Searching for Disease-Modifying Drugs in AD: Can We Combine Neuropsychological Tools with Biological Markers?
CNS & Neurological Disorders - Drug Targets Nanostructured Lipid Carriers (NLCs) for Drug Delivery: Role of Liquid Lipid (Oil)
Current Drug Delivery Association Between Immunologic and Virologic Functioning and Health-Related Quality of Life Among People Living with HIV, Tehran, Iran
Infectious Disorders - Drug Targets Estrous Cycle and HIV-1 Tat Protein Influence Cocaine-Conditioned Place Preference and Induced Locomotion of Female Mice
Current HIV Research Predictive QSAR Modeling Workflow, Model Applicability Domains, and Virtual Screening
Current Pharmaceutical Design Patent Selections:
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery Graphical Abstracts:
Current Neuropharmacology Benzodiazepine Metabolism: An Analytical Perspective
Current Drug Metabolism Biological Drugs in Guillain-Barré Syndrome: An Update
Current Neuropharmacology Endocrine Disruptors and Human Health
Mini-Reviews in Medicinal Chemistry Presynaptic Release-regulating Metabotropic Glutamate Receptors: An Update
Current Neuropharmacology Reactive Astrocytes as Potential Manipulation Targets in Novel Cell Replacement Therapy of Parkinsons Disease
Current Drug Targets Neuropsychiatric Properties of the ACE2/Ang-(1-7)/Mas Pathway: A Brief Review
Protein & Peptide Letters Bicyclic 6 + 6 Systems: Advances in the Chemistry of Heterocyclic Compounds Incorporated Pyrimido[1,2-a]Pyrimidine Skeleton
Mini-Reviews in Organic Chemistry Alcohol Abuse and HIV Infection: Role of DRD2
Current HIV Research Recent Progress in the Development of Subtype Selective Nicotinic Acetylcholine Receptor Ligands
Current Drug Targets - CNS & Neurological Disorders Application of Glutathione as Anti-Oxidative and Anti-Aging Drugs
Current Drug Metabolism Biomarkers for Alzheimer's Disease Diagnosis
Current Alzheimer Research