Stereoselective Synthesis of Conformationally Restricted γ- and β-Amino Alcohols as GluN2B Subtype-Selective NMDA Receptor Antagonists

A series of γ- and β-amino alcohols <b>6</b> and <b>15</b> was designed to restrict the corresponding conformationally flexible substructures found in the prototypical GluN2B-specific NMDA receptor inhibitors Ro 25-6981 (<b>1</b>) and ifenprodil (<b>2</b>). The diastereomerically pure <i>cis</i>- and <i>trans</i>-configured γ-amino alcohols <b>6</b> and β-amino alcohols <b>15</b> were prepared diastereoselectively from bicyclic ketones <b>4</b> and <b>10</b>. Relationships between the structure (ring size, relative configuration, piperidine-OH-distance) and the GluN2B affinity were investigated. Usually, high GluN2B affinity translated into high inhibitory activity at the NMDA receptor. γ-Amino alcohol <i>trans</i>-<b>6c</b> displayed the highest selectivity over both σ receptors but was very fast metabolized <i>in vitro</i>. With respect to GluN2B affinity, inhibitory activity, ligand-lipophilicity efficiency (LLE), selectivity over σ₁ receptors, and metabolic stability, β-amino alcohols <i>cis</i>-<b>15a</b> and <i>trans</i>-<b>15b</b> represent the most promising ligands of this series of compounds. However, both ligands displayed strong interactions with σ₂ receptors indicating poor selectivity towards this receptor type.