Synthesis of conformationally restricted 1,3-dioxanes to analyze the bioactive conformation of 1,3-dioxane-based σ1and PCP receptor antagonists.
The receptor binding profile of 2-phenyl-4-(aminoethyl)-1,3-dioxanes is dependent on the additional substituent in 2-position, the substituents at the amino moiety and the stereochemistry. Herein, conformationally restricted 1,3-dioxanes bearing an axially oriented phenyl moiety in 2-position were prepared and pharmacologically evaluated. Two subsequent intramolecular transacetalization reactions represent the key steps in the synthesis of the tricyclic system. The resulting alcohol 17 was transformed into amines 20-23 with axially (a-series) or equatorially oriented aminoethyl moiety (b-series). The primary amines 20a and 20b did not interact with the PCP binding site of the NMDA receptor, which is explained by the additional methylene moiety between the acetalic center and the phenyl moiety, the missing substituent at the acetalic position and/or a non-optimal three-dimensional arrangement of the pharmacophoric elements. The benzylamine 21b with an equatorially oriented aminoethyl moiety shows high σ1affinity (Ki=5.9nM). Compared with the conformationally flexible 1,3-dioxane 5, the σ1affinity of 21b is 3-fold and the σ1/σ2selectivity is 5-fold increased.
Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.
Samuel
S
Asare-Nkansah
Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.
Dirk
D
Schepmann
Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstraße 48, D-48149 Münster, Germany; Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), Westfälische Wilhelms-Universität Münster, Germany. Electronic address: wuensch@uni-muenster.de.
Bernhard
B
Wünsch
D001665:Binding Sites; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D004146:Dioxanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008968:Molecular Conformation; D066244:Proton Magnetic Resonance Spectroscopy; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D017478:Receptors, Phencyclidine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017480:Receptors, sigma / Q000037:antagonists & inhibitors*; D021241:Spectrometry, Mass, Electrospray Ionization; D017550:Spectroscopy, Fourier Transform Infrared
D004146:Dioxanes; D016194:Receptors, N-Methyl-D-Aspartate; D017478:Receptors, Phencyclidine; D017480:Receptors, sigma
2,6-Epoxy-3-benzoxocines; Amines; Conformationally restricted 1,3-dioxanes; Diastereomers; Intramolecular transacetalization; NMDA receptor; PCP binding site; Receptor selectivity; σ(1) receptor