title: Rigidity versus Flexibility: Is This an Issue in σ1 Receptor Ligand Affinity and Activity?
abstract: Stereoisomeric 2,5-diazabicyclo[2.2.2]octanes 14 and 15 were prepared in a chiral-pool synthesis starting from (S)- or (R)-aspartate. The key step in the synthesis was a Dieckmann-analogous cyclization of (dioxopiperazinyl)acetates 8, which involved trapping of the intermediate hemiketal anion with Me3SiCl. The σ1 affinity was tested using membrane preparations from animal (guinea pig) and human origin. The binding of bicyclic compounds was analyzed by molecular dynamics simulations based on a 3D homology model of the σ1 receptor. The good correlation between Ki values observed in the σ1 assays and calculated free binding energy, coupled with the identification of four crucial ligand/receptor interactions, allowed the formulation of structure-affinity relationships. In an in vitro antitumor assay with seven human tumor cell lines, the bicyclic compounds inhibited selectively the growth of the cell line A427, which is due to induction of apoptosis. In this assay, the compounds behave like the known σ1 receptor antagonist haloperidol.
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, University of Münster , Corrensstraße 48, D-48149 Münster, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Weber
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, University of Münster , Corrensstraße 48, D-48149 Münster, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Brune
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, University of Münster , Corrensstraße 48, D-48149 Münster, Germany.
authors.forename: Frederik
authors.initials: F
authors.lastname: Börgel
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, University of Greifswald , Friedrich-Ludwig-Jahn-Straße 17, 17487 Greifswald, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Lange
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, University of Greifswald , Friedrich-Ludwig-Jahn-Straße 17, 17487 Greifswald, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Korpis
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, University of Greifswald , Friedrich-Ludwig-Jahn-Straße 17, 17487 Greifswald, Germany.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Bednarski
authors.affiliation: Molecular Simulations Engineering (MOSE) Laboratory, Department of Engineering and Architecture (DEA), University of Trieste , Via Valerio 6, 34127 Trieste, Italy.
authors.forename: Erik
authors.initials: E
authors.lastname: Laurini
authors.affiliation: Molecular Simulations Engineering (MOSE) Laboratory, Department of Engineering and Architecture (DEA), University of Trieste , Via Valerio 6, 34127 Trieste, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Fermeglia
authors.affiliation: Molecular Simulations Engineering (MOSE) Laboratory, Department of Engineering and Architecture (DEA), University of Trieste , Via Valerio 6, 34127 Trieste, Italy.|National Interuniversity Consortium for Material Science and Technology (INSTM), Research Unit MOSE-DEA, University of Trieste , Via Valerio 6, 32127 Trieste, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Pricl
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, University of Münster , Corrensstraße 48, D-48149 Münster, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schepmann
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, University of Münster , Corrensstraße 48, D-48149 Münster, Germany.|Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), University of Münster, 48149 Münster, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006168:Guinea Pigs; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017480:Receptors, sigma / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: C000619635:2,5-diazabicyclo(2.2.2)octane; D000970:Antineoplastic Agents; D006574:Heterocyclic Compounds, 2-Ring; D008024:Ligands; D010879:Piperazines; D017480:Receptors, sigma