ABSTRACT
Opioids are powerful analgesics acting via the human µ-opiate receptor (hMOR). Opioid use is associated with adverse effects such as tolerance, addiction, respiratory depression, and constipation. Two synthetic opioids, AH-7921 and U-47700 that were developed in the 1970s but never marketed, have recently appeared on the illegal drug market and in forensic toxicology reports. These agents were initially characterized for their analgesic activity in rodents; however, their pharmacology at hMOR has not been delineated. Thus, we synthesized over 50 chemical analogs based on core AH-7921 and U-47700 structures to assess for their ability to couple to Gαi signaling and induce hMOR internalization. For both the AH-7921 and U-47700 analogs, the 3,4-dichlorobenzoyl substituents were the most potent with comparable EC50 values for inhibition of cAMP accumulation; 26.49 ± 11.2 nmol L-1 and 8.8 ± 4.9 nmol L-1, respectively. Despite similar potencies for Gαi coupling, these two compounds had strikingly different hMOR internalization efficacies: U-47700 (10 µmol L-1) induced ~25% hMOR internalization similar to DAMGO while AH-7921 (10 µmol L-1) induced ~5% hMOR internalization similar to morphine. In addition, the R, R enantiomer of U-47700 is significantly more potent than the S, S enantiomer at hMOR. In conclusion, these data suggest that U-47700 and AH-7921 analogs have high analgesic potential in humans, but with divergent receptor internalization profiles, suggesting that they may exhibit differences in clinical utility or abuse potential.
