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 σ1 affinity (Ki=5.9nM). Compared with the conformationally flexible 1,3-dioxane 5, the σ1 affinity of 21b is 3-fold and the σ1/σ2 selectivity is 5-fold increased.
Keywords: 2,6-Epoxy-3-benzoxocines; Amines; Conformationally restricted 1,3-dioxanes; Diastereomers; Intramolecular transacetalization; NMDA receptor; PCP binding site; Receptor selectivity; σ(1) receptor.
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