Synthesis and Structure-Affinity Relationships of Receptor Ligands with 1,3-Dioxane Structure

Background/Objectives: Ligands blocking σ₁ receptors or NMDA receptors show promising pharmacological properties, such as analgesia or neuroprotection. It had been shown that depending on the stereochemistry and substitution pattern, 1,3-dioxnaes can selectively interact with either σ₁ receptors or the phencyclidine binding site of NMDA receptors. Herein, systematic modifications of homologous aminobutyl substituted 1,3-dioxanes were conducted in order to identify ligands selectively addressing σ receptors or NMDA receptors. Methods: The first step of the synthesis, i.e., the acetalization of benzaldehyde (7a) or propiophenone (7b) with pentane-1,3,5-triol (6), determined the relative configuration of the envisaged 1,3-dioxanes bearing 4-aminobutyl substituents in 4-position. Multi-step homologation of ethanols 8 provided various primary, secondary and tertiary amines 14, 16-19, and 24-27. The affinity towards σ₁ and σ₂ receptors as well as the PCP and ifenprodil binding sites of the NMDA receptor was systematically evaluated in radioligand receptor binding studies. Results: Only the primary amines 14b and 24b derived from propiophenone interacted moderately with the PCP binding site of the NMDA receptor. Within this class of compounds, the N-benzylamines 17 and 18 showed the highest σ₁ affinity with high selectivity over the PCP binding site and at least preference over the σ₂ receptor. The benzylamine 17a (K_i(σ₁) = 31 nM, LLE = 6.19) and the pyrrolidine 19a (K_i(σ₁) = 154 nM, LLE = 6.72) represent the most promising σ₁ ligands of this compound series, when taking the lipophilicity and receptor selectivity into account. Conclusions: Both compounds showed medium metabolic stability in vitro rendering them promising candidates for further studies.