Abstract
The aims of this study were to synthesize 14-O-Methylmorphine-6-O-sulfate (14-O-MeM6SU) and examine its opioid properties (potency, affinity, efficacy) in receptor ligand binding and isolated tissues (mouse vas deferens, MVD and rat vas deferens, RVD bioassays). The results were then compared to the parent compounds morphine-6-O-sulfate (M6SU) and morphine, as well as the µ- opioid receptor (MOR) selective agonist peptide [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin (DAMGO). An additional objective was to compare the effect of subcutaneously (s.c.) or intracerebroventricularly (i.c.v.) administered 14-O-MeM6SU, M6SU and morphine in thermal nociception, rat tail-flick (RTF) test. In MVD, the EC50 (nM) value was 4.38 for 14-O-MeM6SU, 102.81 for M6SU, 346.63 for morphine and 238.47 for DAMGO. The effect of 14-O-MeM6SU and DAMGO was antagonized by naloxone (NAL) with Ke value 1-2.00 nM. The Emax values (%) were 99.10, 36.87, 42.51 and 96.99 for 14-O-MeM6SU, M6SU, morphine and DAMGO, respectively. In RVD 14-O-MeM6SU and DAMGO but not M6SU or morphine showed agonist activity. In binding experiments the affinity of 14-OMeM6SU, M6SU, morphine and DAMGO for MOR was 1.12, 11.48, 4.37 and 3.24 nM, respectively. The selectivity of 14-O-MeM6SU was κ/μ= 269 and δ/μ= 9. In G-protein activation experiments, 14-O-MeM6SU and DAMGO showed higher Emax values than M6SU or morphine. S.c. or i.c.v-injected 14-O-MeM6SU, M6SU and morphine produced a dose and time-dependent increase in RTF response latency. 14-O-MeM6SU was the most potent. Our results showed that introduction of 14-O-Me in M6SU increased the binding affinity, agonist potency, and most importantly, the intrinsic efficacy (Emax).
Keywords: Morphine, DAMGO, DADLE, 14-O-Methylmorphine-6-O-sulfate, receptor binding, MVD, RVD, potency, G-protein activation, intrinsic efficacy, tail flick, analgesia.
Current Medicinal Chemistry
Title:A Novel µ-Opioid Receptor Ligand with High In Vitro and In Vivo Agonist Efficacy
Volume: 19 Issue: 27
Author(s): E. Lacko, A. Varadi, R. Rapavi, F. Zador, P. Riba, S. Benyhe, A. Borsodi, S. Hosztafi, J. Timar, B. Noszal, S. Furst and M. Al-Khrasani
Affiliation:
Keywords: Morphine, DAMGO, DADLE, 14-O-Methylmorphine-6-O-sulfate, receptor binding, MVD, RVD, potency, G-protein activation, intrinsic efficacy, tail flick, analgesia.
Abstract: The aims of this study were to synthesize 14-O-Methylmorphine-6-O-sulfate (14-O-MeM6SU) and examine its opioid properties (potency, affinity, efficacy) in receptor ligand binding and isolated tissues (mouse vas deferens, MVD and rat vas deferens, RVD bioassays). The results were then compared to the parent compounds morphine-6-O-sulfate (M6SU) and morphine, as well as the µ- opioid receptor (MOR) selective agonist peptide [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin (DAMGO). An additional objective was to compare the effect of subcutaneously (s.c.) or intracerebroventricularly (i.c.v.) administered 14-O-MeM6SU, M6SU and morphine in thermal nociception, rat tail-flick (RTF) test. In MVD, the EC50 (nM) value was 4.38 for 14-O-MeM6SU, 102.81 for M6SU, 346.63 for morphine and 238.47 for DAMGO. The effect of 14-O-MeM6SU and DAMGO was antagonized by naloxone (NAL) with Ke value 1-2.00 nM. The Emax values (%) were 99.10, 36.87, 42.51 and 96.99 for 14-O-MeM6SU, M6SU, morphine and DAMGO, respectively. In RVD 14-O-MeM6SU and DAMGO but not M6SU or morphine showed agonist activity. In binding experiments the affinity of 14-OMeM6SU, M6SU, morphine and DAMGO for MOR was 1.12, 11.48, 4.37 and 3.24 nM, respectively. The selectivity of 14-O-MeM6SU was κ/μ= 269 and δ/μ= 9. In G-protein activation experiments, 14-O-MeM6SU and DAMGO showed higher Emax values than M6SU or morphine. S.c. or i.c.v-injected 14-O-MeM6SU, M6SU and morphine produced a dose and time-dependent increase in RTF response latency. 14-O-MeM6SU was the most potent. Our results showed that introduction of 14-O-Me in M6SU increased the binding affinity, agonist potency, and most importantly, the intrinsic efficacy (Emax).
Export Options
About this article
Cite this article as:
Lacko E., Varadi A., Rapavi R., Zador F., Riba P., Benyhe S., Borsodi A., Hosztafi S., Timar J., Noszal B., Furst S. and Al-Khrasani M., A Novel µ-Opioid Receptor Ligand with High In Vitro and In Vivo Agonist Efficacy, Current Medicinal Chemistry 2012; 19 (27) . https://dx.doi.org/10.2174/092986712803306376
DOI https://dx.doi.org/10.2174/092986712803306376 |
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
-
Design and Efficient Synthesis of Novel 4,5-Dimethylthiazole-Hydrazone Derivatives and their Anticancer Activity
Letters in Drug Design & Discovery Active Tumor Targeting of Nanomaterials Using Folic Acid, Transferrin and Integrin Receptors
Current Drug Discovery Technologies (Iso)Flav(an)ones, Chalcones, Catechins, and Theaflavins as Anticarcinogens: Mechanisms, Anti-Multidrug Resistance and QSAR Studies
Current Medicinal Chemistry Targeting CXCL12/CXCR4 Axis in Tumor Immunotherapy
Current Medicinal Chemistry Molecular Approaches Target to Immunotherapy for HPV-Associated Cancers
Current Cancer Drug Targets Recent Patents on Proteasome Inhibitors of Natural Origin
Recent Patents on Anti-Cancer Drug Discovery Fluorine-18 Labeled Amino Acids for Oncologic Imaging with Positron Emission Tomography
Current Topics in Medicinal Chemistry Double-Faced Role of Human Mesenchymal Stem Cells and their Role/Challenges in Cancer Therapy
Current Stem Cell Research & Therapy Pharmacological Targeting of the Hsp70 Chaperone
Current Topics in Medicinal Chemistry PREFACE
Anti-Cancer Agents in Medicinal Chemistry Plant Coumestans: Recent Advances and Future Perspectives in Cancer Therapy
Anti-Cancer Agents in Medicinal Chemistry Expression and Single Nucleotide Polymorphism of Poly (ADPRibose) Polymerase-1 in Gastrointestinal Tumours: Clinical Involvement
Current Medicinal Chemistry Review of Clinic Trials: Agents Targeting c-Met
Reviews on Recent Clinical Trials Alkaloids as Important Scaffolds in Therapeutic Drugs for the Treatments of Cancer, Tuberculosis, and Smoking Cessation
Current Topics in Medicinal Chemistry Tracking Stem Cells for Cellular Therapy in Stroke
Current Pharmaceutical Design Protein Degradation Pathways after Brain Ischemia
Current Drug Targets Redox Regulation in the Base Excision Repair Pathway: Old and New Players as Cancer Therapeutic Targets
Current Medicinal Chemistry Functional Genomics Approaches in Cancer Research
Current Genomics Flavonoids as Anticancer Agents: Recent Progress and State of the Art?
Current Organic Chemistry Recent Advances in Adenovirus-mediated Gene Therapy for Cerebral Ischemia
Current Gene Therapy