Synthesis and evaluation of N-3 substituted phenoxypropyl piperidine benzimidazol-2-one analogues as NOP receptor agonists with analgesic and sedative properties

A series of 3-phenoxypropyl piperidine benzimidazol-2-one analogues have been discovered as novel NOP receptor agonists. Structure–activity relationships have been explored via N-3 substitution of the benzimidazol-2-one with a range of functionality. The N-methyl acetamide derivative (+)-7f was found to be a high-affinity, potent NOP agonist with greater than 100-fold selectivity over the MOP receptor. Furthermore (+)-7f was shown to be both antinociceptive and sedative when administered iv to rodents.

A series of N-3 substituted phenoxypropyl piperidine benzimidazol-2-one analogues were prepared and evaluated as NOP agonists. The selective NOP agonist (+)-7f showed antinociceptive properties in the mouse formalin paw test (ED50 = 1.03 μmol/kg, for second phase) and potent anaesthetic activity in the LRR assay.Figure optionsDownload as PowerPoint slide