67579-11-7Relevant academic research and scientific papers
Synthesis and pharmacological characterization of ethylenediamine synthetic opioids in human μ-opiate receptor 1 (OPRM1) expressing cells
Hsu, Tom,Mallareddy, Jayapal R.,Yoshida, Kayla,Bustamante, Vincent,Lee, Tim,Krstenansky, John L.,Zambon, Alexander C.
, (2019/10/19)
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.
Factors affecting binding of trans-N-[2-(methylamino)cyclohexyl]benzamides at the primary morphine receptor
Cheney,Szmuszkovicz,Lahti,Zichi
, p. 1853 - 1864 (2007/10/02)
In this paper, we describe the synthesis of a series of trans-N-[2-(methylamine)cyclohexyl]benzamides possessing morphine-like pharmacological properties. The affinity of the compounds for the agonist and antagonist states of the μ opioid receptor has been established by means of an in vitro binding assay. We have investigated the geometry and electronic structure of the molecules using molecular mechanics and an ab initio SCF-MO procedure with FSGO basis sets. Comparison to naloxone reveals properties of possible importance in receptor association. We have considered both the S,S and R,R isomers in the binding model. Statistical analyses imply that three factors play a significant role in binding: membrane-water partitioning, the capacity of the aromatic ring and amine N-substituent to act as electron acceptors, the conformational energy required to attain the binding configuration.
