Abstract
The classical benzodiazepines (Bz) constitute a well-known class of therapeutics displaying hypnotic, anxiolytic and anticonvulsant effects acting upon a specific binding site (BzR) belonging to the GABAA receptor complex. Their usefulness, however, is limited by a broad range of side effects; consequently the fact that the action of GABA with the receptor complex could be allosterically modulated by a wide variety of chemical entities, made the Bz binding site, from late eighties to nowdays, the target of extensive research programmes directed to the identification of new ligands displaying varying degrees of affinity- and efficacy-selectivity for the different GABAA/BzR-subtypes. The principal aim has been to discover ideal sedative-hypnotic agents (selective 1 agonists), anxiolytic agents (selective 2/ 3 agonists), or cognitive enhancers (selective 5 inverse agonists). In this connection, an important contribution in the field of GABAA/BzR ligands was made by the research group directed by Professor Antonio Da Settimo at the University of Pisa. The purpose of this review is therefore to describe the studies, performed from early 80s, on the several classes of BzR ligands developed featuring the indol-3-ylglyoxyl scaffold. All the compounds reported have been summarized on the basis of their main chemical structural features, focusing attention on their SARs, which determined the affinity profiles or efficacy-selectivity. Moreover, the biological studies performed within each class of compounds allowed the identification of new derivatives exhibiting an anxiolytic/nonsedative profile, either in vitro (full 2 agonism and 1 partial agonism/ antagonism) and in vivo (anxiolytic/nonsedative activity in mice).
Keywords: Anxiolytic agents, BzR ligands, GABAA/BzR, complex, indolylglyoxylamide, pharmacophore model, structureactivity relationships, benzodiazepines (Bz), hypnotic, anxiolytic and anticonvulsant effects, affinity- and efficacy-selectivity for the different GABAA/BzR-subtypes, indol-3-ylglyoxyl scaffold, anxiolytic/nonsedative profile
Current Topics in Medicinal Chemistry
Title: Medicinal Chemistry of Indolylglyoxylamide GABAA/BzR High Affinity Ligands: Identification of Novel Anxiolytic/Non Sedative Agents
Volume: 12 Issue: 4
Author(s): Silvia Salerno, Federico Da Settimo, Sabrina Taliani, Francesca Simorini, Concettina La Motta, Giacomo Fornaciari and Anna Maria Marini
Affiliation:
Keywords: Anxiolytic agents, BzR ligands, GABAA/BzR, complex, indolylglyoxylamide, pharmacophore model, structureactivity relationships, benzodiazepines (Bz), hypnotic, anxiolytic and anticonvulsant effects, affinity- and efficacy-selectivity for the different GABAA/BzR-subtypes, indol-3-ylglyoxyl scaffold, anxiolytic/nonsedative profile
Abstract: The classical benzodiazepines (Bz) constitute a well-known class of therapeutics displaying hypnotic, anxiolytic and anticonvulsant effects acting upon a specific binding site (BzR) belonging to the GABAA receptor complex. Their usefulness, however, is limited by a broad range of side effects; consequently the fact that the action of GABA with the receptor complex could be allosterically modulated by a wide variety of chemical entities, made the Bz binding site, from late eighties to nowdays, the target of extensive research programmes directed to the identification of new ligands displaying varying degrees of affinity- and efficacy-selectivity for the different GABAA/BzR-subtypes. The principal aim has been to discover ideal sedative-hypnotic agents (selective 1 agonists), anxiolytic agents (selective 2/ 3 agonists), or cognitive enhancers (selective 5 inverse agonists). In this connection, an important contribution in the field of GABAA/BzR ligands was made by the research group directed by Professor Antonio Da Settimo at the University of Pisa. The purpose of this review is therefore to describe the studies, performed from early 80s, on the several classes of BzR ligands developed featuring the indol-3-ylglyoxyl scaffold. All the compounds reported have been summarized on the basis of their main chemical structural features, focusing attention on their SARs, which determined the affinity profiles or efficacy-selectivity. Moreover, the biological studies performed within each class of compounds allowed the identification of new derivatives exhibiting an anxiolytic/nonsedative profile, either in vitro (full 2 agonism and 1 partial agonism/ antagonism) and in vivo (anxiolytic/nonsedative activity in mice).
Export Options
About this article
Cite this article as:
Salerno Silvia, Da Settimo Federico, Taliani Sabrina, Simorini Francesca, La Motta Concettina, Fornaciari Giacomo and Maria Marini Anna, Medicinal Chemistry of Indolylglyoxylamide GABAA/BzR High Affinity Ligands: Identification of Novel Anxiolytic/Non Sedative Agents, Current Topics in Medicinal Chemistry 2012; 12 (4) . https://dx.doi.org/10.2174/156802612799078847
DOI https://dx.doi.org/10.2174/156802612799078847 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...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
-
Imidazoles as Potential Antifungal Agents: A Review
Mini-Reviews in Medicinal Chemistry A Review on Anticancer Potentials of Benzothiazole Derivatives
Mini-Reviews in Medicinal Chemistry Competition Between Tumor and Mononuclear Phagocyte System Causing the Low Tumor Distribution of Nanoparticles and Strategies to Improve Tumor Accumulation
Current Drug Delivery Case Report on Pulmonary Involvement in a Patient with Adult Still’s Disease
Current Rheumatology Reviews Neglected Tropical Protozoan Diseases: Drug Repositioning as a Rational Option
Current Topics in Medicinal Chemistry Sunflower Trypsin Inhibitor 1 as a Molecular Scaffold for Drug Discovery
Current Pharmaceutical Design The Secretin/Pituitary Adenylate Cyclase-Activating Polypeptide/ Vasoactive Intestinal Polypeptide Superfamily in the Central Nervous System
Central Nervous System Agents in Medicinal Chemistry Could Small Neurotoxins-Peptides be Expressed during SARS-CoV-2 Infection?
Current Genomics Recent Medicinal Chemistry Studies for Multitarget Agents-Part II
Current Drug Targets Preparation and Cytotoxic Activities of Fatty Acid Derivatives of 20(S)- Protopanaxatriol
Letters in Drug Design & Discovery Chromone, A Privileged Scaffold in Drug Discovery: Developments in the Synthesis and Bioactivity
Mini-Reviews in Medicinal Chemistry Molecular Targeting of Aberrant Transcription Factors in Leukemia: Strategies for RUNX1/ETO
Current Drug Targets Effects of Hyperlipidemia and Cardiovascular Diseases on Proliferation, Differentiation and Homing of Mesenchymal Stem Cells
Current Stem Cell Research & Therapy T-type Calcium Channels in Health and Disease
Current Medicinal Chemistry Nutritional and Therapeutic Potential of Spirulina
Current Pharmaceutical Biotechnology The Antimitotic Podophyllotoxin and its Derivatives Recent Synthetic Advances
Current Nutraceuticals Inflammation-Induced Thrombosis: Mechanisms, Disease Associations and Management
Current Pharmaceutical Design Preface
Current Pediatric Reviews Structural Aspects of mTOR Inhibitors: Search for Potential Compounds
Anti-Cancer Agents in Medicinal Chemistry Physiology to Disease Transmission of Respiratory Tract Infection: A Narrative Review
Infectious Disorders - Drug Targets