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
![](/images/wayfinder.jpg)
- 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
-
Rethinking Target Discovery in Polygenic Diseases
Current Topics in Medicinal Chemistry Maternal Vitamin D and its Role in Determining Fetal Origins of Mental Health
Current Pharmaceutical Design Body Image Disturbance and Psychopathology in Children: Research Evidence and Implications for Prevention and Treatment
Current Psychiatry Reviews High Throughput Optimization of Stem Cell Microenvironments
Combinatorial Chemistry & High Throughput Screening Advancement of Technology for Drug Discovery and Development – Part II
Current Topics in Medicinal Chemistry Neuropeptide Y as an Endogenous Antiepileptic, Neuroprotective and Pro-Neurogenic Peptide
Recent Patents on CNS Drug Discovery (Discontinued) Neurotrophic Factors - A Tool for Therapeutic Strategies in Neurological,Neuropsychiatric and Neuroimmunological Diseases?
Current Medicinal Chemistry Metal-Score as a Potential Non-Invasive Diagnostic Test for Alzheimer’s Disease
Current Alzheimer Research High Performance and Flexible Configuration Data Acquisition and Processing Unit in All Digital PET System
Neuroscience and Biomedical Engineering (Discontinued) Natural Products to Anti-trypanosomal Drugs: An Overview of New Drug Prototypes for American Trypanosomiasis
Cardiovascular & Hematological Agents in Medicinal Chemistry Crystal Structures of Phosphodiesterases and Implications on Substrate Specificity and Inhibitor Selectivity
Current Topics in Medicinal Chemistry Pharmacological Modulation of the State of Awareness in Patients with Disorders of Consciousness: An Overview
Current Pharmaceutical Design Target-oriented Mechanisms of Novel Herbal Therapeutics in the Chemotherapy of Gastrointestinal Cancer and Inflammation
Current Pharmaceutical Design The Neuropathology of Vascular Disease in the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS)
Current Alzheimer Research The Effects of Combined Omega-3 Fatty Acids and Valproic Acid Supplementation on Symptoms of Borderline Personality Disorder: A Pilot Study
Current Psychopharmacology Promoter Methylation and Gene Expression of Pin1 Associated with the Risk of Alzheimer’s Disease in Southern Chinese
Current Alzheimer Research Lead (Pb) in Alzheimer’s Dementia: A Systematic Review of Human Case- Control Studies
Current Alzheimer Research Nogo Receptor Interacts with Brain APP and Aβ to Reduce Pathologic Changes in Alzheimers Transgenic Mice
Current Alzheimer Research The Quinazoline-Chalcone and Quinazolinone-Chalcone Hybrids: A Promising Combination for Biological Activity
Mini-Reviews in Medicinal Chemistry Current Options in the Treatment of Mitochondrial Diseases
Recent Patents on CNS Drug Discovery (Discontinued)