Abstract
β-Endorphin (β-EP) is generally classified as aμ;andδ;opioid receptor agonist but is also an agonist of theℇ opioid receptor. Although several selective agonists and antagonists for m, d, and k opioid receptors are known, selectiveℇ receptor agonists or antagonists have not been reported for some time. Recently, we designed and synthesized the selectiveℇ receptor agonist, 17-(cyclopropylmethyl)-4,5α-epoxy-3,6β- dihydroxy-6,14-endoethenomorphinan-7α-[N-methyl-N-phenethyl]carboxamide (TAN-821), and the selective e receptor antagonist, 17-(cyclopropylmethyl)-4,5α-epoxy-6b,21-epoxymethano-3-hydroxy-6,14-endoethenomorphinan- 7α-(N-phenethyl)carboxamide (TAN-1014). TAN-821 stimulated binding of the nonhydrolyzable guanosine 5-triphosphate analogue, guanosine 5-(γ-thio)-triphosphate (GTPgS), to the mouse pons/medulla membrane via activation of theℇ receptor. Moreover, TAN-821 given intracerebroventricularly (i.c.v.) produced marked, lonγ;lasting, and dose-dependent antinociception in tail-flick and hot-plate tests. This antinociception induced by i.c.v. administered TAN-821 was blocked by i.c.v. pretreatment with the e opioid receptor partial agonist β-EP (1-27), but not theμ;opioid receptor antagonist β-FNA, theδ;opioid receptor antagonist NTI, or the k opioid receptor antagonist nor-BNI. On the other hand, i.c.v. injection of TAN- 1014 alone produced no antinociception, and i.c.v. pretreatment with TAN-1014 attenuated the antinociception induced by i.c.v β-EP. These results suggest that TAN-821 and TAN-1014 are respectively a selectiveℇ receptor agonist and antagonist and that they may be useful tools for investigating the pharmacological properties of theℇ opioid receptor.
Keywords: e opioid receptor, β-endorphin, TAN-821, TAN-1014, analgesics, message-address concept, accessory site theory
Current Medicinal Chemistry
Title: Rational Drug Design of Selective ℇ Opioid Receptor Agonist TAN-821 and Antagonist TAN-1014
Volume: 13 Issue: 10
Author(s): H. Fujii and H. Nagase
Affiliation:
Keywords: e opioid receptor, β-endorphin, TAN-821, TAN-1014, analgesics, message-address concept, accessory site theory
Abstract: β-Endorphin (β-EP) is generally classified as aμ;andδ;opioid receptor agonist but is also an agonist of theℇ opioid receptor. Although several selective agonists and antagonists for m, d, and k opioid receptors are known, selectiveℇ receptor agonists or antagonists have not been reported for some time. Recently, we designed and synthesized the selectiveℇ receptor agonist, 17-(cyclopropylmethyl)-4,5α-epoxy-3,6β- dihydroxy-6,14-endoethenomorphinan-7α-[N-methyl-N-phenethyl]carboxamide (TAN-821), and the selective e receptor antagonist, 17-(cyclopropylmethyl)-4,5α-epoxy-6b,21-epoxymethano-3-hydroxy-6,14-endoethenomorphinan- 7α-(N-phenethyl)carboxamide (TAN-1014). TAN-821 stimulated binding of the nonhydrolyzable guanosine 5-triphosphate analogue, guanosine 5-(γ-thio)-triphosphate (GTPgS), to the mouse pons/medulla membrane via activation of theℇ receptor. Moreover, TAN-821 given intracerebroventricularly (i.c.v.) produced marked, lonγ;lasting, and dose-dependent antinociception in tail-flick and hot-plate tests. This antinociception induced by i.c.v. administered TAN-821 was blocked by i.c.v. pretreatment with the e opioid receptor partial agonist β-EP (1-27), but not theμ;opioid receptor antagonist β-FNA, theδ;opioid receptor antagonist NTI, or the k opioid receptor antagonist nor-BNI. On the other hand, i.c.v. injection of TAN- 1014 alone produced no antinociception, and i.c.v. pretreatment with TAN-1014 attenuated the antinociception induced by i.c.v β-EP. These results suggest that TAN-821 and TAN-1014 are respectively a selectiveℇ receptor agonist and antagonist and that they may be useful tools for investigating the pharmacological properties of theℇ opioid receptor.
Export Options
About this article
Cite this article as:
Fujii H. and Nagase H., Rational Drug Design of Selective ℇ Opioid Receptor Agonist TAN-821 and Antagonist TAN-1014, Current Medicinal Chemistry 2006; 13 (10) . https://dx.doi.org/10.2174/092986706776360851
DOI https://dx.doi.org/10.2174/092986706776360851 |
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
-
Mesenchymal Stem Cells in the Treatment of Amyotrophic Lateral Sclerosis
Current Stem Cell Research & Therapy Molecular Mechanism of Inhibition of Polysialyltransferase Domain (PSTD) by Heparin
Current Topics in Medicinal Chemistry Molecular Mechanisms, Biological Actions, and Neuropharmacology of the Growth-Associated Protein GAP-43
Current Neuropharmacology Recent Patents on Novel P2X7 Receptor Antagonists and their Potential for Reducing Central Nervous System Inflammation
Recent Patents on CNS Drug Discovery (Discontinued) The Role of Neuropeptides and Neurohormones in Neurogenic Cardiac Arrhythmias
Current Drug Targets - Cardiovascular & Hematological Disorders The Role of Image Guided Radiotherapy in the Treatment of Soft Tissue Sarcoma
Current Cancer Therapy Reviews Chemically Functionalized Carbon Nanotubes: Emerging Vectors for Cell Therapy
Mini-Reviews in Medicinal Chemistry GluN2B/N-methyl-D-aspartate Receptor Antagonists: Advances in Design, Synthesis, and Pharmacological Evaluation Studies
CNS & Neurological Disorders - Drug Targets Recent Advances in Treatment Approaches of Mucopolysaccharidosis VI
Current Pharmaceutical Biotechnology Current Management of Traumatic Rupture of the Descending Thoracic Aorta
Current Cardiology Reviews Multiple Sclerosis and Neuroinflammation: The Overview of Current and Prospective Therapies
Current Pharmaceutical Design On the Use of Hydrogels in Cell Encapsulation and Tissue Engineering Systems
Recent Patents on Drug Delivery & Formulation Therapeutic Targeting of Leukocyte Trafficking Across the Blood-Brain Barrier
Inflammation & Allergy - Drug Targets (Discontinued) Gene Therapy in Cerebrovascular Diseases
Current Gene Therapy CB1 Cannabinoid Receptors and their Associated Proteins
Current Medicinal Chemistry Antimicrobial Peptides Present in Mammalian Skin and Gut are Multifunctional Defence Molecules
Current Pharmaceutical Design A Systematic Review of Selected Musculoskeletal Late Effects in Survivors of Childhood Cancer
Current Pediatric Reviews Human Umbilical Cord Mesenchymal Stem Cell Therapy on Neuromyelitis Optica
Current Neurovascular Research Cell-Replacement Therapy with Stem Cells in Neurodegenerative Diseases
Current Neurovascular Research Nutraceutical-based Integrative Medicine: Adopting a Mediterranean Diet Pyramid for Attaining Healthy Ageing in Veterans with Disabilities
Current Pharmaceutical Design