Design, Synthesis, Pharmacological Evaluation and Docking Studies of GluN2B-Selective NMDA Receptor Antagonists with a Benzo[7]annulen-7-amine Scaffold. 2017

Sandeep Gawaskar, and Louisa Temme, and Julian A Schreiber, and Dirk Schepmann, and Alessandro Bonifazi, and Dina Robaa, and Wolfgang Sippl, and Nathalie Strutz-Seebohm, and Guiscard Seebohm, and Bernhard Wünsch
Institut für Pharmazeutische und Medizinische Chemie der, Universität Münster, Corrensstraße 48, 48149, Münster, Germany.

Antagonists that selectively target GluN2B-subunit-containing N-methyl-d-aspartate (NMDA) receptors are of major interest for the treatment of various neurological disorders. In this study, relationships between variously substituted benzo[7]annulen-7-amines and their GluN2B affinity were investigated. 2-Nitro-5,6,8,9-tetrahydrobenzo[7]annulen-7-one (8) represents the central building block for the introduction of various substituents at the 2-position and various 7-amino moieties. N-(3-Phenylpropyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-amines with a 2-NO2 (7 c), 2-Cl (15 c), or 2-OBn group (22 c) show very high GluN2B affinity (Ki =1.6-3.6 nm). Docking studies revealed the same binding poses for benzo[7]annulen-7-amines and ifenprodil at the interface of GluN1b and GluN2B subunits. The large 2-OBn moiety of 22 c occupies a previously unrecognized subpocket, which explains its high GluN2B affinity (Ki =3.6 nm). In two-electrode voltage clamp experiments and cytoprotection assays, the high-affinity GluN2B ligands 7 c, 15 c, and 22 c could not inhibit the glutamate-/glycine-evoked current and cytotoxic effects. However, the analogous phenols 16 c ((3-phenylpropyl)amino moiety) and 16 d ((4-phenylbutyl)amino moiety) with 10-fold lower GluN2B affinity (Ki =28 and 21 nm, respectively) showed promising inhibition of glutamate-/glycine-evoked effects in both assays. The presence of a phenolic hydroxy group seems to be essential for inducing conformational changes of the receptor protein, which finally results in closure of the ion conduction pathway.

UI MeSH Term Description Entries
D004307 Dose-Response Relationship, Radiation The relationship between the dose of administered radiation and the response of the organism or tissue to the radiation. Dose Response Relationship, Radiation,Dose-Response Relationships, Radiation,Radiation Dose-Response Relationship,Radiation Dose-Response Relationships,Relationship, Radiation Dose-Response,Relationships, Radiation Dose-Response
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D001567 Benzocycloheptenes Compounds consisting of the cycloheptene ring with one or two BENZENE rings fused to it.
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D015195 Drug Design The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include PHARMACOKINETICS, dosage analysis, or drug administration analysis. Computer-Aided Drug Design,Computerized Drug Design,Drug Modeling,Pharmaceutical Design,Computer Aided Drug Design,Computer-Aided Drug Designs,Computerized Drug Designs,Design, Pharmaceutical,Drug Design, Computer-Aided,Drug Design, Computerized,Drug Designs,Drug Modelings,Pharmaceutical Designs
D015394 Molecular Structure The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. Structure, Molecular,Molecular Structures,Structures, Molecular
D016194 Receptors, N-Methyl-D-Aspartate A class of ionotropic glutamate receptors characterized by affinity for N-methyl-D-aspartate. NMDA receptors have an allosteric binding site for glycine which must be occupied for the channel to open efficiently and a site within the channel itself to which magnesium ions bind in a voltage-dependent manner. The positive voltage dependence of channel conductance and the high permeability of the conducting channel to calcium ions (as well as to monovalent cations) are important in excitotoxicity and neuronal plasticity. N-Methyl-D-Aspartate Receptor,N-Methyl-D-Aspartate Receptors,NMDA Receptor,NMDA Receptor-Ionophore Complex,NMDA Receptors,Receptors, NMDA,N-Methylaspartate Receptors,Receptors, N-Methylaspartate,N Methyl D Aspartate Receptor,N Methyl D Aspartate Receptors,N Methylaspartate Receptors,NMDA Receptor Ionophore Complex,Receptor, N-Methyl-D-Aspartate,Receptor, NMDA,Receptors, N Methyl D Aspartate,Receptors, N Methylaspartate
D062105 Molecular Docking Simulation A computer simulation technique that is used to model the interaction between two molecules. Typically the docking simulation measures the interactions of a small molecule or ligand with a part of a larger molecule such as a protein. Molecular Docking,Molecular Docking Simulations,Molecular Docking Analysis,Analysis, Molecular Docking,Docking Analysis, Molecular,Docking Simulation, Molecular,Docking, Molecular,Molecular Docking Analyses,Molecular Dockings,Simulation, Molecular Docking

Related Publications

Sandeep Gawaskar, and Louisa Temme, and Julian A Schreiber, and Dirk Schepmann, and Alessandro Bonifazi, and Dina Robaa, and Wolfgang Sippl, and Nathalie Strutz-Seebohm, and Guiscard Seebohm, and Bernhard Wünsch
June 2019, Journal of labelled compounds & radiopharmaceuticals,
Sandeep Gawaskar, and Louisa Temme, and Julian A Schreiber, and Dirk Schepmann, and Alessandro Bonifazi, and Dina Robaa, and Wolfgang Sippl, and Nathalie Strutz-Seebohm, and Guiscard Seebohm, and Bernhard Wünsch
April 2014, ChemMedChem,
Sandeep Gawaskar, and Louisa Temme, and Julian A Schreiber, and Dirk Schepmann, and Alessandro Bonifazi, and Dina Robaa, and Wolfgang Sippl, and Nathalie Strutz-Seebohm, and Guiscard Seebohm, and Bernhard Wünsch
January 2018, European journal of medicinal chemistry,
Sandeep Gawaskar, and Louisa Temme, and Julian A Schreiber, and Dirk Schepmann, and Alessandro Bonifazi, and Dina Robaa, and Wolfgang Sippl, and Nathalie Strutz-Seebohm, and Guiscard Seebohm, and Bernhard Wünsch
August 2018, ChemMedChem,
Sandeep Gawaskar, and Louisa Temme, and Julian A Schreiber, and Dirk Schepmann, and Alessandro Bonifazi, and Dina Robaa, and Wolfgang Sippl, and Nathalie Strutz-Seebohm, and Guiscard Seebohm, and Bernhard Wünsch
December 2014, Bioorganic & medicinal chemistry,
Sandeep Gawaskar, and Louisa Temme, and Julian A Schreiber, and Dirk Schepmann, and Alessandro Bonifazi, and Dina Robaa, and Wolfgang Sippl, and Nathalie Strutz-Seebohm, and Guiscard Seebohm, and Bernhard Wünsch
September 2018, European journal of medicinal chemistry,
Sandeep Gawaskar, and Louisa Temme, and Julian A Schreiber, and Dirk Schepmann, and Alessandro Bonifazi, and Dina Robaa, and Wolfgang Sippl, and Nathalie Strutz-Seebohm, and Guiscard Seebohm, and Bernhard Wünsch
January 2020, Bioorganic & medicinal chemistry,
Sandeep Gawaskar, and Louisa Temme, and Julian A Schreiber, and Dirk Schepmann, and Alessandro Bonifazi, and Dina Robaa, and Wolfgang Sippl, and Nathalie Strutz-Seebohm, and Guiscard Seebohm, and Bernhard Wünsch
January 2021, CNS & neurological disorders drug targets,
Sandeep Gawaskar, and Louisa Temme, and Julian A Schreiber, and Dirk Schepmann, and Alessandro Bonifazi, and Dina Robaa, and Wolfgang Sippl, and Nathalie Strutz-Seebohm, and Guiscard Seebohm, and Bernhard Wünsch
December 2015, Bioorganic & medicinal chemistry letters,
Sandeep Gawaskar, and Louisa Temme, and Julian A Schreiber, and Dirk Schepmann, and Alessandro Bonifazi, and Dina Robaa, and Wolfgang Sippl, and Nathalie Strutz-Seebohm, and Guiscard Seebohm, and Bernhard Wünsch
August 2019, Journal of pharmaceutical and biomedical analysis,
Copied contents to your clipboard!