Synthesis and structural characterization of spiroxatrine derivatives as potential non-peptide ligands for NOP receptor

Nociceptin or orphanin FQ peptide (N/OFQ) was identified in 1995 as the endogenous ligand for the opioid receptor ORL-1, actually denominated NOP, a fourth member of the classical μ, δ and κ opioid receptors family. N/OFQ-NOP system is implicated in several biological functions, such as in pain modulation. Therefore, NOP receptor represents an interesting target for the development of new therapeutical agentsagainst the acute cancer pain. On the basis of the confirmed affinity towards NOP receptor of the alpha2 adrenergic and 5-HT1A partial agonist spiroxatrine(Ki= 127 nM), we focused our attention on the design, synthesis and characterization of novel NOP receptor ligands with a spiropiperidine portion. The aim was to study the effects of some structural modifications on the 1,4-benzodioxane moiety ofspiroxatrine. In particular, we carried out: 1) isosteric replacement of C8 with a nitrogen atom; 2) disconnection of 1-8a and 4-4a bonds of spiroxatrine and of its nitrogen isosteres to give derivatives with a primary or a secondary alcoholic group respectively (2-5); 3) replacement of 1,4-benzodioxane moiety of spiroxatrine with a 1-benzhydryloxy-propan-2-ol and 2-benzhydryloxy-propan-1-ol moiety in order to increase the steric hindrance (6-7). Retrosynthetic strategies for compounds 1-7 are shown in the following schemes. Compounds 1-7 will be subjected to biological activity assays.