Synthesis and NMDA-receptor affinity of ring and side chain homologous dexoxadrol derivatives

Abstract

The regioselectivity during transacetalization of benzophenone dimethyl acetal (4) with butane-1,2,4-triol (5) is controlled by the reaction conditions. Thermodynamic control leads predominantly to the 1,3-dioxolane 6 whereas kinetic control favors the six-membered acetal 7. The amines 2a-e and 3a-e are synthesized from the alcohols 6 and 7 and are investigated in receptor binding studies with radioligands for their affinity to the phencyclidine binding site of the NMDA-receptor. In both series the primary amines 2 a and 3a show the highest NMDA-receptor affinity (2a: Ki = 3.38 μM; 3a: K i = 1.45 μM). The NMDA receptor slightly prefers the 1,3-dioxane derivatives 3a and 3b compared to 2a and 2b (factor 2-3). Low interactions of the amines 3a and 3b with various receptor and reuptake systems indicate selectivity for the NMDA receptor. Surprisingly, the piperidine derivative 2e binds with high affinity at σ1-receptors and, therefore, represents a novel lead compound for high affinity σ1-receptor ligands.