New mu-opioid receptor agonists with phenoxyacetic acid moiety.
New muq-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, 12-[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 delta- and kappa-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.
Sato
Susumu
S
Central Research Laboratories SSP Co, Ltd, Narita, Chiba, Japan. Susumu.Sato@ssp.co.jp
Komoto
Teruo
T
Kanamaru
Yoshihiko
Y
Kawamoto
Noriyuki
N
Okada
Tomomi
T
Kaiho
Terumitsu
T
Mogi
Kinichi
K
Morimoto
Shinichi
S
Umehara
Norimitsu
N
Koda
Tadayuki
T
Miyashita
Akira
A
Sakamoto
Takao
T
Niino
Yasuhiro
Y
Oka
Tetsuo
T
D000701:Analgesics, Opioid / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000819:agonists*
D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu