Enantiomerically Pure 1,3-Dioxanes as Highly Selective NMDA and σ₁ Receptor Ligands

We synthesized and investigated the NMDA and σ₁ receptor affinity of enantiomerically pure 2-(2-phenyl-1,3-dioxan-4-yl)­ethanamines <b>17</b>–<b>26</b>. The primary amines (<i>R</i>,<i>R</i>)-<b>18</b>–<b>20</b> with an axially oriented phenyl moiety in position 2 interacted with high enantioselectivity (eudismic ratios 70–130) and high affinity (<i>K</i>_i((<i>R</i>,<i>R</i>)-<b>19</b>) = 13 nM) with the PCP binding site of the NMDA receptor. Introduction of an <i>N</i>-benzyl moiety led to potent σ₁ ligands including compound (<i>S</i>,<i>R</i>)-<b>22</b> (<i>K</i>_i = 6 nM) with an equatorially oriented phenyl moiety in position 2