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

<b>Background/Objectives</b>: 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. <b>Methods</b>: The first step of the synthesis<i>,</i> i.e., the acetalization of benzaldehyde (<b>7a</b>) or propiophenone (<b>7b</b>) with pentane-1,3,5-triol (<b>6</b>), determined the relative configuration of the envisaged 1,3-dioxanes bearing 4-aminobutyl substituents in 4-position. Multi-step homologation of ethanols <b>8</b> provided various primary, secondary and tertiary amines <b>14</b>, <b>16</b>-<b>19</b>, and <b>24</b>-<b>27</b>. 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. <b>Results</b>: Only the primary amines <b>14b</b> and <b>24b</b> derived from propiophenone interacted moderately with the PCP binding site of the NMDA receptor. Within this class of compounds, the <i>N</i>-benzylamines <b>17</b> and <b>18</b> showed the highest σ₁ affinity with high selectivity over the PCP binding site and at least preference over the σ₂ receptor. The benzylamine <b>17a</b> (<i>K</i>_i(σ₁) = 31 nM, LLE = 6.19) and the pyrrolidine <b>19a</b> (<i>K</i>_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. <b>Conclusions</b>: Both compounds showed medium metabolic stability in vitro rendering them promising candidates for further studies.