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 6 and 15 was designed to restrict the corresponding conformationally flexible substructures found in the prototypical GluN2B-specific NMDA receptor inhibitors Ro 25-6981 (1) and ifenprodil (2). The diastereomerically pure cis- and trans-configured γ-amino alcohols 6 and β-amino alcohols 15 were prepared diastereoselectively from bicyclic ketones 4 and 10. 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 trans-6c displayed the highest selectivity over both σ receptors but was very fast metabolized in vitro. With respect to GluN2B affinity, inhibitory activity, ligand-lipophilicity efficiency (LLE), selectivity over σ1 receptors, and metabolic stability, β-amino alcohols cis-15a and trans-15b 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.