Novel Delta Opioid Receptor Agonists with Oxazatricyclodecane Structure

We synthesized compounds 4a,c–f,h,i containing the oxazatricyclodecane structure from a novel rearrangement reaction product 2a. All the prepared compounds 4a,c–f,h,i exhibited full agonistic activities for the δ opioid receptor (DOR). Among them, the N-methyl derivative 4c was highly selective, and the most effective DOR agonist in functional assays. Subcutaneous administration of 4c produced dose-dependent and NTI (selective DOR antagonist)-reversible antinociception lacking any convulsive behaviors in the mice acetic acid writhing tests. The N-methyl derivative 4c is expected to be a promising lead compound for selective DOR agonists with a novel chemotype.