Opioid Receptor Modulators with a Cinnamyl Group

To obtain selective
and potent opioid receptor ligands, we synthesized
dehydro derivatives of alvimopan and found compound (28f), a selective but modest affinity MOR antagonist weaker than alvimopan
(1). We replaced the arylpiperidine unit by an arylpiperazine
to obtain the 1-(α-carboxycinnamyl)-4-arylpiperazines like 13h, which to our surprise had no MOR or DOR activity but
was a KOR agonist with moderate affinity. In contrast, literature
examples of arylpiperazines 4 and 5 were
reported to be pan opioid receptor antagonists, while 6 was a MOR agonist. Two compounds (13l and 11b) showed analgesic response in tail flick test which was blocked
by pretreatment with norbinaltorphimine (norBNI). Among 10 1-(α-carboxycinnamyl)-4-arylpiperidines,
compound 28g and five others were specific MOR antagonists.
Interestingly, compound 26b of this series was found
to be more potent than naloxone but weaker than 1. Docking
studies have explained differential activities of the above piperazines
and piperidines.