title: Design, synthesis and receptor affinity of novel conformationally restricted σ ligands based on the [4.3.3]propellane scaffold.
abstract: A series of novel diastereoisomeric σ ligands 3 was designed, synthesized and pharmacologically evaluated. The highly rigid [4.3.3]propellane scaffold was used to fix the three dimensional orientation of the pharmacophoric moieties required for σ affinity. The syn,syn-configured aminocarbamate syn,syn-3a reveals the most promising σ₁ affinity (Ki = 77 nM) and selectivity over the σ₂ subtype (21-fold). The σ₂ affinity of all four diastereomers 3 was in the low micromolar range. Analysis of the distance between the hydrophobic regions (phenyl moieties) of the diastereomers 3 led to the longest range of distances (10.3-15.2 Å) for the most potent σ₁ ligand syn,syn-3a, which is in good agreement with pharmacophore models.
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.
authors.forename: Héctor
authors.initials: H
authors.lastname: Torres-Gómez
authors.forename: Kirstin
authors.initials: K
authors.lastname: Lehmkuhl
authors.forename: Dirk
authors.initials: D
authors.lastname: Schepmann
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
mesh_terms: D000818:Animals; D001921:Brain; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006168:Guinea Pigs; D008024:Ligands; D008099:Liver / Q000737:chemistry; D008968:Molecular Conformation; D051381:Rats; D017480:Receptors, sigma / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C000591461:(4.3.3)propellane-8,11-dione; D001952:Bridged-Ring Compounds; D008024:Ligands; D017480:Receptors, sigma
keywords: Conformational restriction; Pharmacophore models; Stereoselective reduction; [4.3.3]Propellane; σ Ligands