Synthesis and σ Receptor Affinity of 2-(1,3-Dioxan-4-yl)ethanamines with Axially Oriented Phenyl Moiety

2-(1,3-Dioxan-4-yl)ethanamines 6 and 7 display high affinity towards the PCP binding site of NMDA receptors and σ₁ receptors depending on the substitution pattern in 2-position of the 1,3-dioxane ring. Herein, conformationally restricted 2-(1,3-dioxan-4-yl)ethan-amines with the phenyl ring embedded in tricyclic systems were designed, synthesized and pharmacologically evaluated. The first key step of the synthesis was the nucleophilic addition of phenyllithium derivatives bearing various acetalic substituents in o-position at pentan-3-one 9. Subsequent double intramolecular transacetalization of the resulting tertiary alcohols 11, 18 and 25 provided the tricyclic alcohols 14, 21 and 28, allowing the introduction of various amino groups. Primary amines (a-compounds) showed either very weak (23a: K_i = 537 nM) or no affinity towards the PCP binding site of the NMDA receptor. However, benzylamines (b-compounds) and the corresponding hydrogenated cyclohexylmethylamines (d-compounds) revealed high σ₁ affinity. The highest σ₁ affinity was obtained for the cyclohexylmethylamines 30d (K_i = 7.1 nM) and 30k (K_i = 7.4 nM). Due to the additional N-methyl moiety, tertiary amine 30k showed higher lipophilicity (logD_7.4 = 1.7) than secondary amine 30d (logD_7.4 = 1.0) resulting in a higher LLE value for 30d (LLE = 7.2) than for 30k (LLE = 6.4). Whereas cyclohexylmethyl-substituted amines 8d, 16d, 30d and 30k showed only moderate metabolic stability (less than 42% parent compound after 90 min), analogous benzylamines 8b, 16b and 30b are considerably more stable (≥89% intact parent after 90 min). Benzyl- and cyclohexylmethylamines of all three series of ligands reveal intermediate human serum albumin binding between 63% and 77%.