Forcing the phenyl moiety into the axial position by embedding the 2-phenyl-1,3-dioxane system in a tricyclic benzomorphan scaffold: design, synthesis and biological evaluation

Abstract

The relative configuration and the substitution pattern control the interaction of 2-(2-phenyl1,3-dioxan-4-yl)ethan-1-amines with σ₁ receptors or the PCP binding site of NMDA receptors. In order to investigate the influence of the orientation of the phenyl moiety in 2-position on the receptor interaction, the 2-phenyl-1,3-dioxane system was embedded in a tricyclic benzomorphan scaffold (3) fixing the phenyl moiety in an axial orientation relative to the 1,3-dioxane ring. The key step of the synthesis of tricyclic amines 3 was the addition of lithiated 2-methylbenzamide 7 at pentanone 6 to afford the tertiary alcohol 8. Lactone formation (9), DIBAH reduction (10) and intramolecular transacetalization led to the tricyclic alcohol 11, which was converted into a series of twelve primary, secondary and tertiary amines 3a–m. Although the primary amine 3a is structurally related to the potent PCP antagonist 2a, it did not interact with the PCP binding site of the NMDA receptor. The missing ethyl moiety and/or an unfavorable orientation of the phenyl moiety might be responsible for the lost PCP affinity of 3a. As observed for the flexible 1,3-dioxanes 1b and 2b, introduction of a benzyl moiety at the amino group resulted in high σ₁ receptor affinity of 3b. In accordance with σ₁ pharmacophore models, two small or two large substituents at the amino moiety were less tolerated by the σ₁ receptor, whereas an additional small methyl moiety increased the σ₁ affinity of 3h and 3j. With respect to σ₁ receptor affinity and selectivity over the σ₂ subtype, the methylated cyclohexylmethylamine 3j (K_i(σ₁) = 6.4 nM, 9-fold selectivity) represents the most promising ligand. The highest ligand-lipophilicity efficiency (LLE) was obtained for the secondary cyclohexylmethylamine 3d (LLE = 6.7). However, the highest metabolic stability (phase I metabolism) was determined for the benzylamine 3b (89% intact after incubation for 90 min).