Abstract
Several classes of compounds that have no intrinsic activity on aminergic systems nonetheless enhance the potency of aminergic receptor ligands three-fold or more while significantly increasing their duration of activity, preventing tachyphylaxis and reversing fade. Enhancer compounds include ascorbic acid, ethylenediaminetetraacetic acid, corticosteroids, opioid peptides, opiates and opiate antagonists. This paper provides the first review of aminergic enhancement, demonstrating that all enhancers have a common, inobvious molecular motif and work through a common mechanism that is manifested by three common characteristics. First, aminergic enhancers bind directly to the amines they enhance, suggesting that the common structural motif is reflected in common binding targets. Second, one common target is the first extracellular loop of aminergic receptors. Third, at least some enhancers are antiphosphodiesterases. These observations suggest that aminergic enhancers act on the extracellular surface of aminergic receptors to keep the receptor in its high affinity state, trapping the ligand inside the receptor. Enhancer binding produces allosteric modifications of the receptor structure that interfere with phosphorylation of the receptor, thereby inhibiting down-regulation of the receptor. The mechanism explains how enhancers potentiate aminergic activity and increase duration of activity and makes testable predictions about additional compounds that should act as aminergic enhancers.
Keywords: aldosterone, allosteric, allostery, antiphosphodiesterase, ascorbic acid, corticosteroid, dopamine, down-regulation, EDTA, enhancement, enhances, epinephrine, GPCR, histamine, increased potency, molecular complementarity, morphine, naloxone, naltrexone, norepinephrine, opiate, opioid, phosphodiesterase inhibitors, potentiates, potentiation, serotonin, supersensitivity, vitamin C.
Current Medicinal Chemistry
Title:A Common Molecular Motif Characterizes Extracellular Allosteric Enhancers of GPCR Aminergic Receptors and Suggests Enhancer Mechanism of Action
Volume: 21 Issue: 32
Author(s): Robert Root-Bernstein and Patrick F. Dillon
Affiliation:
Keywords: aldosterone, allosteric, allostery, antiphosphodiesterase, ascorbic acid, corticosteroid, dopamine, down-regulation, EDTA, enhancement, enhances, epinephrine, GPCR, histamine, increased potency, molecular complementarity, morphine, naloxone, naltrexone, norepinephrine, opiate, opioid, phosphodiesterase inhibitors, potentiates, potentiation, serotonin, supersensitivity, vitamin C.
Abstract: Several classes of compounds that have no intrinsic activity on aminergic systems nonetheless enhance the potency of aminergic receptor ligands three-fold or more while significantly increasing their duration of activity, preventing tachyphylaxis and reversing fade. Enhancer compounds include ascorbic acid, ethylenediaminetetraacetic acid, corticosteroids, opioid peptides, opiates and opiate antagonists. This paper provides the first review of aminergic enhancement, demonstrating that all enhancers have a common, inobvious molecular motif and work through a common mechanism that is manifested by three common characteristics. First, aminergic enhancers bind directly to the amines they enhance, suggesting that the common structural motif is reflected in common binding targets. Second, one common target is the first extracellular loop of aminergic receptors. Third, at least some enhancers are antiphosphodiesterases. These observations suggest that aminergic enhancers act on the extracellular surface of aminergic receptors to keep the receptor in its high affinity state, trapping the ligand inside the receptor. Enhancer binding produces allosteric modifications of the receptor structure that interfere with phosphorylation of the receptor, thereby inhibiting down-regulation of the receptor. The mechanism explains how enhancers potentiate aminergic activity and increase duration of activity and makes testable predictions about additional compounds that should act as aminergic enhancers.
Export Options
About this article
Cite this article as:
Root-Bernstein Robert and Dillon F. Patrick, A Common Molecular Motif Characterizes Extracellular Allosteric Enhancers of GPCR Aminergic Receptors and Suggests Enhancer Mechanism of Action, Current Medicinal Chemistry 2014; 21 (32) . https://dx.doi.org/10.2174/0929867321666140826120604
DOI https://dx.doi.org/10.2174/0929867321666140826120604 |
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
-
Can Tea Consumption be a Safe and Effective Therapy Against Diabetes Mellitus-Induced Neurodegeneration?
Current Neuropharmacology Development of Novel Therapeutic Strategies for Lung Cancer: Targeting the Cholinergic System
Current Medicinal Chemistry Inhibition of Voltage-Gated Calcium Channels by RGK Proteins
Current Molecular Pharmacology Aldose Reductase / Polyol Inhibitors for Diabetic Retinopathy
Current Pharmaceutical Biotechnology The Role of Selenium in Oxidative Stress and in Nonthyroidal Illness Syndrome (NTIS): An Overview
Current Medicinal Chemistry The DREAM of Pain Relief
Current Rheumatology Reviews Statin Therapy
Current Pharmaceutical Design Ghrelin in Obesity, Physiological and Pharmacological Considerations
Mini-Reviews in Medicinal Chemistry The Potential Role of Pro-Inflammatory and Anti-Inflammatory Cytokines in Epilepsy Pathogenesis
Endocrine, Metabolic & Immune Disorders - Drug Targets Editorial [Hot Topic: Drug Metabolisms Associated with Human Microbiome (Guest Editor: Chun-Ming Huang) ]
Current Drug Metabolism Histamine as a Potential Adjuvant to Immuno and Radiotherapy for Cancer Treatment: Discovering New Functions for the Oldest Biogenic Amine
Current Immunology Reviews (Discontinued) FoxO Transcription Factors and Regenerative Pathways in Diabetes Mellitus
Current Neurovascular Research Anticoagulant Therapy in Very Old Patients
Cardiovascular & Hematological Disorders-Drug Targets Flavonoids and the Brain: Evidences and Putative Mechanisms for a Protective Capacity
Current Neuropharmacology Patent Selections:
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery INNO-206 (DOXO-EMCH), an Albumin-Binding Prodrug of Doxorubicin Under Development for Phase II Studies
Current Bioactive Compounds Potential Roles of MyomiRs in Cardiac Development and Related Diseases
Current Cardiology Reviews Triiodothyronine (T3) Effects on Cardiovascular System in Patients with Heart Failure
Recent Patents on Cardiovascular Drug Discovery Implications of IFN-γ-Mediated Tryptophan Catabolism on Solid Organ Transplantation
Current Drug Metabolism NADPH Oxidases in the Heart
Current Cardiology Reviews