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

Background/Objectives : Ligands blocking σ 1 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 σ 1 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 σ 1 and σ 2 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 σ 1 affinity with high selectivity over the PCP binding site and at least preference over the σ 2 receptor. The benzylamine 17a ( K i (σ 1 ) = 31 nM, LLE = 6.19) and the pyrrolidine 19a ( K i (σ 1 ) = 154 nM, LLE = 6.72) represent the most promising σ 1 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.