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 (Ki(σ1) = 31 nM, LLE = 6.19) and the pyrrolidine 19a (Ki(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.