Abstract
The serotonin transporter protein (SERT) has been the target for the development of several modern antidepressants with an objective of achieving selectivity over other monoamine transporters, thereby minimising side effects observed in the older generation of tricyclic antidepressants. The clinical selective serotonin reuptake inhibitors (SSRIs) have been shown to be among the most effective therapies in the treatment of depression. However they have clinical disadvantages over other classes of antidepressant drugs such as slow onset of action nausea and sleep disruption. The negative feedback loop attributed to the presynaptic 5-HT1A receptors has been implicated in the “time lag” observed in many patients between the administration of the SSRI and its observed therapeutic action. In recent years the focus has been on developing compounds with dual affinity for serotonergic auto-receptors along with an inhibitory activity at SERT. These structurally diverse products promise to be the next generation of anti-depressant medicines. This review presents an analysis of the recently reported structural classes with SSRI activity and rationalises the unique relationship between their molecular properties and biological activities. Specific emphasis is placed on the development of molecular structures with dual serotonergic activity. Recent advances in the design and synthesis of single molecular entities possessing 5-HT reuptake inhibition together with 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, DAT, NET, α2-adrenoceptor and acetylcholinesterase antagonism are reviewed. The structural studies to identify proposed SERT binding sites together with the role of structure and ligand based design in the development of more effective SSRIs are summarised.
Keywords: Anti-depressants, selective serotonin reuptake inhibitors, SERT pharmacophores, dual action serotonergic antidepressants
Current Medicinal Chemistry
Title: Recent Developments in the Design of Anti-Depressive Therapies: Targeting the Serotonin Transporter
Volume: 15 Issue: 17
Author(s): S. G. Butler and M. J. Meegan
Affiliation:
Keywords: Anti-depressants, selective serotonin reuptake inhibitors, SERT pharmacophores, dual action serotonergic antidepressants
Abstract: The serotonin transporter protein (SERT) has been the target for the development of several modern antidepressants with an objective of achieving selectivity over other monoamine transporters, thereby minimising side effects observed in the older generation of tricyclic antidepressants. The clinical selective serotonin reuptake inhibitors (SSRIs) have been shown to be among the most effective therapies in the treatment of depression. However they have clinical disadvantages over other classes of antidepressant drugs such as slow onset of action nausea and sleep disruption. The negative feedback loop attributed to the presynaptic 5-HT1A receptors has been implicated in the “time lag” observed in many patients between the administration of the SSRI and its observed therapeutic action. In recent years the focus has been on developing compounds with dual affinity for serotonergic auto-receptors along with an inhibitory activity at SERT. These structurally diverse products promise to be the next generation of anti-depressant medicines. This review presents an analysis of the recently reported structural classes with SSRI activity and rationalises the unique relationship between their molecular properties and biological activities. Specific emphasis is placed on the development of molecular structures with dual serotonergic activity. Recent advances in the design and synthesis of single molecular entities possessing 5-HT reuptake inhibition together with 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, DAT, NET, α2-adrenoceptor and acetylcholinesterase antagonism are reviewed. The structural studies to identify proposed SERT binding sites together with the role of structure and ligand based design in the development of more effective SSRIs are summarised.
Export Options
About this article
Cite this article as:
Butler G. S. and Meegan J. M., Recent Developments in the Design of Anti-Depressive Therapies: Targeting the Serotonin Transporter, Current Medicinal Chemistry 2008; 15 (17) . https://dx.doi.org/10.2174/092986708784872357
DOI https://dx.doi.org/10.2174/092986708784872357 |
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
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
Current advances in inherited cardiomyopathy
Describe in detail all novel advances in multimodality imaging related to inherited cardiomyopathy diagnosis and prognosis. Shed light to deeper phenotypic characterization. Acknowledge recent advances in genetics, genomics and precision medicineread 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
-
Pharmacological Exploitation of Indole-3-Carbinol to Develop Potent Antitumor Agents
Mini-Reviews in Medicinal Chemistry Arachidonate Cascade in the Intensive Insulin Therapy for Critically Ill Patients with Sepsis: Roles of Prostaglandins on Hyperglycemia-Impaired Immunity
Letters in Drug Design & Discovery Review of Recent Patents on Foldable Ventricular Assist Devices
Recent Patents on Biomedical Engineering (Discontinued) The Ubiquitin-Proteasome System as a Prospective Molecular Target for Cancer Treatment and Prevention
Current Protein & Peptide Science Pharmacophore Generation and 3D-QSAR of Novel 2-(quinazolin-4- ylamino)-[1,4] Benzoquinone Derivatives as VEGFR-2 Inhibitors
Letters in Drug Design & Discovery Induced Pluripotent Stem Cell-Based Studies of Parkinson's Disease: Challenges and Promises
CNS & Neurological Disorders - Drug Targets Molecular Modeling Studies, Synthesis and Biological Evaluation of Novel Plasmodium falciparum Lactate Dehydrogenase (pfLDH) Inhibitors
Anti-Infective Agents Thiazolidinediones Anti-Inflammatory and Anti-Atherosclerotic Effects in Type 2 Diabetes Mellitus
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Nitric Oxide and Oral Diseases: Can We Talk About It?
Cardiovascular & Hematological Agents in Medicinal Chemistry Snake Venom Induced Local Toxicities: Plant Secondary Metabolites as an Auxiliary Therapy
Mini-Reviews in Medicinal Chemistry Calcium-engaged Mechanisms of Nongenomic Action of Neurosteroids
Current Neuropharmacology Accumulation and Membrane Transport of Plant Alkaloids
Current Pharmaceutical Biotechnology An update on Anti-inflammatory Compounds: A Review
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry New Chitosan Nanospheres for the Delivery of 5-Fluorouracil: Preparation, Characterization and in vitro Studies
Current Drug Delivery Matrix Metalloproteinases: New Routes to the Use of MT1-MMP As A Therapeutic Target in Angiogenesis-Related Disease
Current Pharmaceutical Design Budesonide and Phenethyl Isothiocyanate Attenuate DNA Damage in Bronchoalveolar Lavage Cells of Mice Exposed to Environmental Cigarette Smoke
Current Cancer Drug Targets PepT1, ASBT-Linked Prodrug Strategy to Improve Oral Bioavailability and Tissue Targeting Distribution
Current Drug Metabolism The Role of Celecoxib as a Potential Inhibitor in the Treatment of Inflammatory Diseases - A Review
Current Medicinal Chemistry Surface Modification of Nanocarriers for Cancer Therapy
Current Nanoscience Modulation of Eosinophil Functions by Nitric Oxide: Cyclic GMPdependent and -independent Mechanisms
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry