AIDS caused by the infection of HIV is a prevalent problem today. Rapid development of drug resistance to existing drug classes has called for the discovery of new targets. Within the three major enzymes (i.e., HIV-1 protease, HIV-1 reverse transcriptase and HIV-1 integrase [IN]) of the viral replication cycle, HIV-1 IN has been of particular interest due to the absence of human cellular homolog. HIV-1 IN catalyzes the integration of viral genetic material with the host genome, a key step in the viral replication process. Several novel classes of HIV IN inhibitors have been explored by targeting different sites on the enzyme. This review strives to provide readers with updates on the recent developments of HIV-1 IN inhibitors.
This study reports on new proteolytically stable, pharmacologically active endomorphin analogues, incorporating Dmt(1), Achc(2), pFPhe(4), or βMePhe(4) unnatural amino acids. Consistent with earlier results, it was found that the analogues carrying Dmt(1) and Achc(2) residues displayed the highest μ-opioid receptor affinities, depending upon the configuration of the incorporated Achc(2). Combination of such derivatives with pFPhe(4) or βMePhe(4) yielded further compounds with variable binding potencies. Combined application of Dmt(1), cis-(1S,2R)Achc(2), and pFPhe(4) (compound 16) resulted in the most potent analogue. Ligand stimulated [(35)S]GTPγS binding assays indicated that the analogues retained their agonist activities and opioid receptor specificities. NMR and molecular modeling studies of the analogues containing βMePhe(4) or pFPhe(4) confirmed the predominance of bent structures, however, it is apparent that bent structures are energetically more favored than random/extended structures for all studied compounds.
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.
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