Azepinone as a conformational constraint in the design of κ-opioid receptor agonists

A new class of κ-opioid receptor agonists is described. The design of these agents was based upon energy minimization and structural overlay studies of the generic azepin-2-one structure 3 with the crystal structure of arylacetamide κ agonist 1, ICI 199441. The most active compound identified was ligand 4a (Ki=0.34nM), which demonstrated potent antinociceptive activity after oral administration in rodents.