Synthesis and Pharmacological Evaluation of a Potent and Selective σ1 Receptor Antagonist with High Antiallodynic Activity

Based on the pharmacophore model of Glennon the conformationally restricted sigma(1) receptor ligand 2 with a 1,3-dioxane moiety has been designed and synthesized. The three step synthesis (transacetalization with pentane-1,3,5-triol, tosylation, and nucleophilic substitution with benzylamine) provided diastereoselectively the cis-configured 1,3-dioxane 2 in good yields. The 1,3-dioxane 2 represents a potent sigma(1) receptor ligand (K-i = 19 nM) with moderate selectivity over the sigma(2) subtype (K-i = 92 nM) and excellent selectivity against more than 60 other targets. Additionally the hERG K+ channel is not affected by 2. In the capsaicin assay 2 showed extraordinarily high analgesic activity with more than 70% analgesia at the very low dose of 0.25 mg/kg body weight, which indicates sigma(1) antagonistic activity. Since 2 does only interact with sigma(1) receptors, the in-vivo antiallodynic activity of 2 must be attributed to the sigma(1) antagonistic activity.