16499-30-2Relevant articles and documents
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.
2-AMINO-1-PHENYLETHYLCARBOXAMIDE DERIVATIVES
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Page/Page column 50, (2008/06/13)
The present invention relates to compounds of formula (I), or to salts or solvates thereof, their use in the manufacture of medicaments for treating neurological and neuropsychiatric disorders, in particular psychoses, dementia or attention deficit disorder. The invention further comprises processes to make these compounds and pharmaceutical formulations thereof. Formula (I) wherein R1 is a group selected from: Formulas (A), (B), (C)
Serotoninergic properties of new conformationally restricted benzamides
Yang,Bremont,Shen,Kefi,Langlois
, p. 231 - 239 (2007/10/03)
A new series of benzamides derived from metoclopramide have been synthesized, in which the vicinal carbon of the basic nitrogen atom of the ethyl chain is situated on the C3, C4, C5 and C6 rings. The diamino derivatives were prepared through Strecker's reaction from the corresponding ketones except for the cyclopropyl derivatives where 1-ethoxy-1-trimethylsiloxy cyclopropane was used as the starting material. The benzamides were prepared using the mixed anhydride method. They were tested in binding assays for D2, 5-HT3 and 5-HT4 receptors. The results show a marked increase in the selectivity and potency of these derivatives for 5-HT3 receptors with regard to metoclopramide (compound 1d: 5-HT3 K(i) = 9.03 nM; 5-HT4 K(i) > 5000; D2 K(i) > 5000). The influences of steric hindrance and hydrophobic properties on the affinity of benzamide derivatives for 5-HT3 receptors were also emphasized by these data. The X-ray crystal structure of compound 1d was compared with that of the minimal energy conformer of BRL 24682, a reference 5-HT3 receptor antagonist benzamide, determined using the Random Search program. Superimposition of the two structures showed a suitable fit between the pharmacophore groups previously determined to be important for 5-HT3 receptor antagonists. On the other hand, the hydrophobic parts of the basic moieties had different spatial occupancies.
