New μ-opioid receptor (MOR) agonists containing 4-hydroxypiperidine, piperidine and piperazine moieties were synthesized and evaluated to find a peripheral opioid analgesic. Among the synthesized compounds, [2-[1-[3-(N,N-dimethylcarbamoyl)-3,3-diphenylpropyl]-4-hydroxypiperidin-4-yl]phenoxy]acetic acid (8: SS620) having phenoxyacetic acid and 4-hydroxypiperidine moieties showed the highest agonist potency on the MOR in an isolated guinea-pig ileum preparation, and it also had selectivity to the human MOR expressed in Chinese hamster ovary (CHO)-K1 cells compared with the same types of δ- and κ-opioid receptors (DOR and KOR). In addition, compound 8 showed a 10 times more potent MOR agonist activity than loperamide. Furthermore, compound 8 showed a peripheral analgesic activity in vivo screening on rat.
2002 The Pharmaceutical Society of Japan