American Chemical Society
jm7b00643_si_001.pdf (9.67 MB)

Opioid Receptor Modulators with a Cinnamyl Group

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journal contribution
posted on 2017-07-20, 00:00 authored by Lokesh Ravilla, N. Venkata subba Naidu, Shalini Dogra, Deepmala Umrao, Prem N. Yadav, Ansuman Biswas, Daliah Michael, Kanagaraj Sekar, Kuppuswamy Nagarajan
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.