Synthesis and pharmacological characterization of ethylenediamine synthetic opioids in human μ‐opiate receptor 1 (OPRM1) expressing cells

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 Gα i 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 EC 50 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 Gα i 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.

U-47700 and Its Analogs: Non-Fentanyl Synthetic Opioids Impacting the Recreational Drug Market

“…Molecular mechanics and ab initio calculations carried out with the U-47700 enantiomers found that the trans (1R,2R) stereoisomer fits perfectly into the MOR binding site, even with a slightly reduced strain energy [ 16 ]. A recent study by Hsu et al [ 39 ] examined the in vitro MOR activity of the U-47700 stereoisomers using a cyclic adenosine monophosphate (cAMP) accumulation assay and confirmed that the trans (1R,2R) stereoisomer (EC 50 = 8.8 nM) is much more potent than the trans (1S,2S) stereoisomer (EC 50 ~1 μM). Investigations into the stereochemistry of U-50488 demonstrate that both the cis isomers display a complete loss of affinity for KOR but show a corresponding increase in affinity for other receptor systems, including sigma receptors [ 40 ] and D2-dopamine receptors [ 38 ].…”

“…MOR/KOR selectivity is influenced by the N -amido substituents as well. For example, the removal of the methyl group to a secondary amide, as in U-47109, results in a 50-fold loss in MOR affinity when compared to U-47700 (although see Hsu et al [ 39 ]). In conclusion, compounds from both the U-47700 series and the U-50488 series possess two hydrophobic sites (cyclohexyl and phenyl moieties) and two polar sites (amino and amido nitrogens).…”

Molecular Mechanisms of Action of Novel Psychoactive Substances (NPS). A New Threat for Young Drug Users with Forensic-Toxicological Implications

“…Affinity to opioid receptors significantly differs between stereoisomers, e.g., only the trans form has opioid activity for U-47700 and U-50488 [ 27 ], and R-enantiomers are thought to be more potent than the S ones [ 29 ]. Even though the in vitro efficacy and potency of several new compounds, such as AP-237, bromadol, brorphine, tianeptine, isotonitazene, and piperidylthiambuetene, has been characterized [ 9 , 30 ], their exact psychopharmacological and neurotoxicological profiles remain scarcely known [ 25 ].…”

Trace Residue Identification, Characterization and Longitudinal Monitoring of the Novel Synthetic Opioid β-U10, from Discarded Drug Paraphernalia

“…However, Hsu et. al., who investigated a range of U-and A-series compounds interacting with human μ-opioid receptor 1 expressing cells [52], reported that α-U10 had no observable agonistic effects. Szmuszkovicz reported that conversion of benzamides to acetamides resulted in reduced µ-receptor activity whilst still retaining analgesic properties, leading to the observation that the modification may result in increased selectivity for the κ-receptor [68].…”

“…retrieved from a report by Hsu et. al[52]. Further searching located a monograph in the SWGDrugdatabase [53] containing characterization data for α-U10 including GC-MS, NMR and FT-IR, but no ESI-MS/MS spectrum.…”