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 σ 1 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 σ 2 receptors indicating poor selectivity towards this receptor type.