Abstract
Three new trishomocubane analogues based on the 4-azahexacyclo[5.4.1.02,6.03,10.05,9.08,11] dodecane-3-ol skeleton have been synthesised and assessed for their affinities at both sigma-1 and sigma-2 receptors. The effect of various N-substitution on the polycyclic moiety was examined. All synthesised compounds displayed high affinity for sigma-1 receptors (9-10 nM) and good affinity for sigma-2 receptors (230-310 nM), suggesting that substitution at the nitrogen moiety of the trishomocubane is well tolerated and represents a platform for the development of improved higher affinity sigma receptor ligands. The interaction of these functionalised trishomocubanes on the binding of the known sigma receptor radioligand, 4-[123I]IBP, was evaluated in the rat brain. Although 4-[123I]IBP had been used for imaging sigma receptors in tumours, this is the first examination of sigma receptor binding in the rat brain and therefore the potential of 4-[123I]IBP for imaging the brain was also evaluated. In vivo specificity and selectivity of 4-[123I]IBP binding was examined by studying the effects of preadministration of sigma receptor binding drugs (+)-pentazocine and unlabelled 4-IBP. This resulted in a blockade of only 42% of 4-[123I]IBP uptake in the brain indicating high degree of non-specific binding suggesting that it may not be suitable for imaging sigma receptors in the brain. The inhibition of 4-[123I]IBP uptake using the two of the three trishomocubanes displayed a consistent blockade of 48-30% in all brain structures. This demonstrates for the first time the ability of functionalised trishomocubanes to interact with sigma receptors in vivo.
Keywords: trishomocubane, sigma receptor, iodine-123, cns
Medicinal Chemistry
Title: Influence of Trishomocubanes on Sigma Receptor Binding of N-(1-Benzylpiperidin- 4-yl)-4-[123I]iodobenzamide In Vivo in the Rat Brain
Volume: 1 Issue: 1
Author(s): Xiang Liu, Filomena Mattner, Andrew Katsifis, MacDonald Christie and Michael Kassiou
Affiliation:
Keywords: trishomocubane, sigma receptor, iodine-123, cns
Abstract: Three new trishomocubane analogues based on the 4-azahexacyclo[5.4.1.02,6.03,10.05,9.08,11] dodecane-3-ol skeleton have been synthesised and assessed for their affinities at both sigma-1 and sigma-2 receptors. The effect of various N-substitution on the polycyclic moiety was examined. All synthesised compounds displayed high affinity for sigma-1 receptors (9-10 nM) and good affinity for sigma-2 receptors (230-310 nM), suggesting that substitution at the nitrogen moiety of the trishomocubane is well tolerated and represents a platform for the development of improved higher affinity sigma receptor ligands. The interaction of these functionalised trishomocubanes on the binding of the known sigma receptor radioligand, 4-[123I]IBP, was evaluated in the rat brain. Although 4-[123I]IBP had been used for imaging sigma receptors in tumours, this is the first examination of sigma receptor binding in the rat brain and therefore the potential of 4-[123I]IBP for imaging the brain was also evaluated. In vivo specificity and selectivity of 4-[123I]IBP binding was examined by studying the effects of preadministration of sigma receptor binding drugs (+)-pentazocine and unlabelled 4-IBP. This resulted in a blockade of only 42% of 4-[123I]IBP uptake in the brain indicating high degree of non-specific binding suggesting that it may not be suitable for imaging sigma receptors in the brain. The inhibition of 4-[123I]IBP uptake using the two of the three trishomocubanes displayed a consistent blockade of 48-30% in all brain structures. This demonstrates for the first time the ability of functionalised trishomocubanes to interact with sigma receptors in vivo.
Export Options
About this article
Cite this article as:
Liu Xiang, Mattner Filomena, Katsifis Andrew, Christie MacDonald and Kassiou Michael, Influence of Trishomocubanes on Sigma Receptor Binding of N-(1-Benzylpiperidin- 4-yl)-4-[123I]iodobenzamide In Vivo in the Rat Brain, Medicinal Chemistry 2005; 1 (1) . https://dx.doi.org/10.2174/1573406053402541
DOI https://dx.doi.org/10.2174/1573406053402541 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
Call for Papers in Thematic Issues
Carbohydrates in Computational and Medicinal Chemistry
Carbohydrates are the most essential organic molecules and are involved in the maintenance of various physiological and metabolic processes in living organisms. Carbohydrate-based compounds have come to the attention of researchers because of their significant contributions to biological functions, such as cell development and cell proliferation, connections between several cells, ...read more
Recent Advances in the Medicinal Chemistry of Cancer
Scope of the Thematic Issue: Correlation between structure and function is one of the important aspects of the success of anti-cancer compounds associated with their structure-activity interactions, physiology, biochemical, molecular, and genetic processes. Overcoming these obstacles is key to obtaining further insights into developments in rational drug design, bioorganic chemistry, ...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
Related Articles
-
Brain Innate Immunity in the Regulation of Neuroinflammation: Therapeutic Strategies by Modulating CD200-CD200R Interaction Involve the Cannabinoid System
Current Pharmaceutical Design Protein Kinase C Pharmacology: Perspectives on Therapeutic Potentials as Antidementic and Cognitive Agents
Recent Patents on CNS Drug Discovery (Discontinued) Cancer Gene Therapy with Tissue Inhibitors of Metalloproteinases (TIMPs)
Current Gene Therapy Cyclin-Dependent Kinase 4/6 (Cdk4/6) Inhibitors: Perspectives in Cancer Therapy and Imaging
Mini-Reviews in Medicinal Chemistry <sup>68</sup>Ga-labeled HBED-CC Variant of uPAR Targeting Peptide AE105 Compared with <sup>68</sup>Ga-NODAGA-AE105
Anti-Cancer Agents in Medicinal Chemistry Impaired Autophagy Mediates Resistance to Low-Dose Metronomic Cyclophosphamide Chemotherapy
Clinical Cancer Drugs P-Glycoprotein and Breast Cancer Resistance Protein Affect Disposition of Tandutinib, A Tyrosine Kinase Inhibitor
Drug Metabolism Letters System Models, Assays and Endpoint Parameters to Evaluate Anticancer Compounds During Preclinical Screening
Current Medicinal Chemistry Diffusion-Weighted MRI for Assessment of Early Cancer Treatment Response
Current Pharmaceutical Biotechnology Co-delivery Strategies Based on Multifunctional Nanocarriers for Cancer Therapy
Current Drug Metabolism Clinical Experiment of Mutant Herpes Simplex Virus HF10 Therapy for Cancer
Current Cancer Drug Targets The Impact of Oxidative Stress on Islet Transplantation and Monitoring the Graft Survival by Non-Invasive Imaging
Current Medicinal Chemistry Cytotoxic, Antiproliferative and Apoptotic Effects of New Benzimidazole Derivatives on A549 Lung Carcinoma and C6 Glioma Cell Lines
Anti-Cancer Agents in Medicinal Chemistry Preoperative Functional Magnetic Resonance Imaging (fMRI) and Transcranial Magnetic Stimulation (TMS)
Current Medical Imaging Targeting p73 - a Potential Approach in Cancer Treatment
Current Pharmaceutical Design Water and Ion Channels: Crucial in the Initiation and Progression of Apoptosis in Central Nervous System?
Current Neuropharmacology NOTCH Signaling as a Novel Cancer Therapeutic Target
Current Cancer Drug Targets Role of Hydrogen Sulfide and Polysulfides in Neurological Diseases: Focus on Protein S-Persulfidation
Current Neuropharmacology Role of Mismatch Repair and MGMT in Response to Anticancer Therapies
Anti-Cancer Agents in Medicinal Chemistry Towards Human on a Chip: Recent Progress and Future Perspective
Micro and Nanosystems