Abstract
A remarkable diversity of psychiatric and neurological disorders have been associated with dysfunction of dopamine (DA)-containing neurons, including schizophrenia, bipolar disorder (BD), Parkinsons disease (PD), and restless legs syndrome (RLS). In such disorders, transmission in discrete DA pathways may range from hypoactivation to hyperactivation of DA receptors, particularly those of the D2 subtype, providing the rationale for treatment approaches that activate or block D2 receptors, respectively. However, full agonists or pure D2 receptor antagonists may not be optimal therapeutic approaches for their respective disorders for a number of reasons, including an inability to restore the aberrant DA pathways to a normal level of basal tone. D2 receptor partial agonists (D2PAs) are proposed to stabilize activity in DA pathways by dampening excessive (and/or by restoring deficient) D2 receptor stimulation thereby shepherding DA neurons back to a desired level of basal activity. Stabilizing aberrant DA activity without disrupting nondysfunctional DA neurons may provide a potentially improved approach for treating DA disorders. The status of DA D2PAs and their potential application to schizophrenia, BD, PD, and RLS is reviewed. Preclinical and clinical evidence supports the idea that dysfunctions of D2 receptors contribute to these CNS disorders. Diseases in which both hyper- and hypofunction of DA pathways are present may be particularly promising, and challenging, targets for D2PAs. Furthermore, different DA disorders may respond optimally to D2PAs with differing levels of intrinsic activity, with “DA deficiency” diseases responding more effectively to higher intrinsic activity D2PAs than “DA hyperactivation” diseases. Overall, current evidence supports the conclusion that D2PAs have significant potential as improved CNS therapies relative to classic full agonists and antagonists at D2 receptors.
Keywords: Dopamine, DA: D2 Receptor Partial Agonist, D2 PA, Dopamine Stabilizer, Aripiprazole, Bifeprunox, periodic limb movements in sleep (PLMS), Aplindore, Schizophrenia, Bipolar Disorder
Current Topics in Medicinal Chemistry
Title: D2 Receptor Partial Agonists: Treatment of CNS Disorders of Dopamine Function
Volume: 8 Issue: 12
Author(s): John H. Kehne, Terrance H. Andree and Julia N. Heinrich
Affiliation:
Keywords: Dopamine, DA: D2 Receptor Partial Agonist, D2 PA, Dopamine Stabilizer, Aripiprazole, Bifeprunox, periodic limb movements in sleep (PLMS), Aplindore, Schizophrenia, Bipolar Disorder
Abstract: A remarkable diversity of psychiatric and neurological disorders have been associated with dysfunction of dopamine (DA)-containing neurons, including schizophrenia, bipolar disorder (BD), Parkinsons disease (PD), and restless legs syndrome (RLS). In such disorders, transmission in discrete DA pathways may range from hypoactivation to hyperactivation of DA receptors, particularly those of the D2 subtype, providing the rationale for treatment approaches that activate or block D2 receptors, respectively. However, full agonists or pure D2 receptor antagonists may not be optimal therapeutic approaches for their respective disorders for a number of reasons, including an inability to restore the aberrant DA pathways to a normal level of basal tone. D2 receptor partial agonists (D2PAs) are proposed to stabilize activity in DA pathways by dampening excessive (and/or by restoring deficient) D2 receptor stimulation thereby shepherding DA neurons back to a desired level of basal activity. Stabilizing aberrant DA activity without disrupting nondysfunctional DA neurons may provide a potentially improved approach for treating DA disorders. The status of DA D2PAs and their potential application to schizophrenia, BD, PD, and RLS is reviewed. Preclinical and clinical evidence supports the idea that dysfunctions of D2 receptors contribute to these CNS disorders. Diseases in which both hyper- and hypofunction of DA pathways are present may be particularly promising, and challenging, targets for D2PAs. Furthermore, different DA disorders may respond optimally to D2PAs with differing levels of intrinsic activity, with “DA deficiency” diseases responding more effectively to higher intrinsic activity D2PAs than “DA hyperactivation” diseases. Overall, current evidence supports the conclusion that D2PAs have significant potential as improved CNS therapies relative to classic full agonists and antagonists at D2 receptors.
Export Options
About this article
Cite this article as:
Kehne H. John, Andree H. Terrance and Heinrich N. Julia, D2 Receptor Partial Agonists: Treatment of CNS Disorders of Dopamine Function, Current Topics in Medicinal Chemistry 2008; 8 (12) . https://dx.doi.org/10.2174/156802608785161394
DOI https://dx.doi.org/10.2174/156802608785161394 |
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
-
The Utilization of Gene Targeting Models During in Preclinical Study of Drug Discovery Process - Example of Phenotypic and Functional Analysis of Cacna1 βGene Product
Current Pharmaceutical Biotechnology Chondroitin Sulfate Glycosaminoglycans for CNS Homeostasis-Implications for Material Design
Current Medicinal Chemistry The Role of Autophagy: What can be Learned from the Genetic Forms of Amyotrophic Lateral Sclerosis
CNS & Neurological Disorders - Drug Targets The Neurobiological Mechanisms and Treatments of REM Sleep Disturbances in Depression
Current Neuropharmacology Nuclear Medicine: Proof of Principle for Targeted Drugs in Diagnosis and Therapy
Current Pharmaceutical Design Adhesion Molecules as Targets for the Treatment of Neoplastic Diseases
Current Pharmaceutical Design Inhibition of Human Serine Racemase, an Emerging Target for Medicinal Chemistry
Current Drug Targets Dreams and Psychedelics: Neurophenomenological Comparison and Therapeutic Implications
Current Neuropharmacology Cannabinoid System in Neurodegeneration: New Perspectives in Alzheimers Disease
Mini-Reviews in Medicinal Chemistry Protein/ Hormone Based Nanoparticles as Carriers for Drugs Targeting Protein-Protein Interactions
Current Topics in Medicinal Chemistry Minimizing AED Adverse Effects: Improving Quality of Life in the Interictal State in Epilepsy Care
Current Neuropharmacology Multidrug Resistance: Retrospect and Prospects in Anti-Cancer Drug Treatment
Current Medicinal Chemistry Psychosocial Factors and Central Sensitivity Syndromes
Current Rheumatology Reviews Applications of Biophysical Tools to Target-Based Discovery of Novel Antibacterial Leads
Current Drug Targets Restoration of the Striatal Dopamine Synthesis for Parkinsons Disease:Viral Vector-Mediated Enzyme Replacement Strategy
Current Gene Therapy Intracerebral Hemorrhage and Diabetes Mellitus: Blood-Brain Barrier Disruption, Pathophysiology and Cognitive Impairments
CNS & Neurological Disorders - Drug Targets G Protein-Coupled Receptor Kinase 2 - a Feedback Regulator of Gq Pathway Signalling
Current Drug Targets - Immune, Endocrine & Metabolic Disorders Drugs Treatment of Pain in Multiple Sclerosis
Current Clinical Pharmacology An Outline of the Historical and Clinical Aspects of Catatonic Schizophrenia
Current Psychiatry Reviews Commentary: Hot, Hotter, and Hottest Trends in α-Synuclein Research
Current Protein & Peptide Science