Abstract
It was postulated that N6-allyl bicyclic derivatives 1 bind with N-8 at the proton donor site of the σ1 receptor and that a substituent in 2-position of the bicyclic framework 1 results in unfavorable steric interactions with the σ1 receptor protein. In order to support this hypothesis both enantiomers of 6-allyl-8-(4-methoxybenzyl)-6,8-diazabicyclo[ 3.2.2]non-2-ene (2/ent-2) and 6-benzyl-8-(4-methoxybenzyl)-6,8-diazabicyclo[3.2.2]nonane 3/ent-3 were synthesized stereoselectively. The (S,S)-configured enantiomers 2 and 3 are the eutomers with eudismic ratios of 31 and 4.8, respectively. Therefore, these enantiomers are used in the σ1 pharmacophore model. The N6-allyl derivative 2 with a double bond in the three carbon bridge adopts the orientation 2c with N-8 interacting with the σ1 receptor proton donor site (Fig. 2) resulting in slightly reduced steric interactions of the small double bond in 2/3-position. The almost C2-symmetric benzyl derivative 3 can adopt both orientations 2c and 2d at the σ1 receptor (N-8 or N-6 interacts with the σ 1 receptor proton donor site) resulting in subnanomolar σ1 receptor affinity (Ki = 0.91 nM).
Keywords: ??1 receptor ligands: 6,8-diazabicyclo[3.2.2]nonanes, 6,8-diazabicyclo[3.2.2]nonenes, pharmacophore model
Central Nervous System Agents in Medicinal Chemistry
Title: Structure-Affinity-Relationship Study of Bicyclic σ Receptor Ligands
Volume: 9 Issue: 3
Author(s): Ralph Holl, Christian Geiger, Masakazu Nambo, Kenichiro Itami, Dirk Schepmann and Bernhard Wunsch
Affiliation:
Keywords: ??1 receptor ligands: 6,8-diazabicyclo[3.2.2]nonanes, 6,8-diazabicyclo[3.2.2]nonenes, pharmacophore model
Abstract: It was postulated that N6-allyl bicyclic derivatives 1 bind with N-8 at the proton donor site of the σ1 receptor and that a substituent in 2-position of the bicyclic framework 1 results in unfavorable steric interactions with the σ1 receptor protein. In order to support this hypothesis both enantiomers of 6-allyl-8-(4-methoxybenzyl)-6,8-diazabicyclo[ 3.2.2]non-2-ene (2/ent-2) and 6-benzyl-8-(4-methoxybenzyl)-6,8-diazabicyclo[3.2.2]nonane 3/ent-3 were synthesized stereoselectively. The (S,S)-configured enantiomers 2 and 3 are the eutomers with eudismic ratios of 31 and 4.8, respectively. Therefore, these enantiomers are used in the σ1 pharmacophore model. The N6-allyl derivative 2 with a double bond in the three carbon bridge adopts the orientation 2c with N-8 interacting with the σ1 receptor proton donor site (Fig. 2) resulting in slightly reduced steric interactions of the small double bond in 2/3-position. The almost C2-symmetric benzyl derivative 3 can adopt both orientations 2c and 2d at the σ1 receptor (N-8 or N-6 interacts with the σ 1 receptor proton donor site) resulting in subnanomolar σ1 receptor affinity (Ki = 0.91 nM).
Export Options
About this article
Cite this article as:
Holl Ralph, Geiger Christian, Nambo Masakazu, Itami Kenichiro, Schepmann Dirk and Wunsch Bernhard, Structure-Affinity-Relationship Study of Bicyclic σ Receptor Ligands, Central Nervous System Agents in Medicinal Chemistry 2009; 9 (3) . https://dx.doi.org/10.2174/1871524910909030220
DOI https://dx.doi.org/10.2174/1871524910909030220 |
Print ISSN 1871-5249 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6166 |
- 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
-
Genomic and Pharmacogenomic Biomarkers of Parkinson’s Disease
Current Drug Metabolism Combined Therapies for Lysosomal Storage Diseases
Current Molecular Medicine Emerging Use of Nanotechnology in the Treatment of Neurological Disorders
Current Pharmaceutical Design Immune System Modulators with Antidepressant Effects: Evidence from Animal Models
CNS & Neurological Disorders - Drug Targets O-Arylation of Iodophenols with 2-Fluorobenzaldehyde Under Microwave Conditions
Letters in Drug Design & Discovery GABA-A Receptor Complex and Memory Processes
Medicinal Chemistry Reviews - Online (Discontinued) Imidazole Incorporated Semicarbazone Derivatives as a New Class of Anticonvulsants: Design, Synthesis and In-Vivo Screening
Medicinal Chemistry Clonazepam for the Treatment of Panic Disorder
Current Drug Targets Interleukin-1β Plays a Role in the Activation of Peripheral Leukocytes after Blood-Brain Barrier Rupture in the Course of Subarachnoid Hemorrhage
Current Neurovascular Research Manipulation of Intracellular pH in Cancer Cells by NHE1 Inhibitors
Protein & Peptide Letters Cannabis sativa L. Constituents and Their Role in Neuroinflammation
Current Bioactive Compounds Classical Neurotransmitters and Neuropeptides Involved in Generalized Epilepsy: A Focus on Antiepileptic Drugs
Current Medicinal Chemistry Zebrafish as an Animal Model to Study Epileptic Seizures and Epileptic Syndromes
Current Psychopharmacology Repositioning of Drugs in Cardiometabolic Disorders: Importance and Current Scenario
Current Topics in Medicinal Chemistry Natural Products as Modulators of Spermatogenesis: The Search for a Male Contraceptive
Current Molecular Pharmacology How to Find Candidate Drug-targets for Antiepileptogenic Therapy?
Current Neuropharmacology What is the Role of Lithium in Epilepsy?
Current Neuropharmacology Crosstalk Between Calpain and Calcineurin in Excitotoxic Neurodegeneration; Therapeutic Targets for the Treatment of Excitotoxic Neurodegeneration
Current Medicinal Chemistry - Central Nervous System Agents Dexmedetomidine Use in General Anaesthesia
Current Drug Targets Pharmacological Targeting of IDO-Mediated Tolerance for Treating Autoimmune Disease
Current Drug Metabolism