Chloroacryloyl amides and alpha-methylenelactones from naltrexone, oxymorphone and fentanyl

A series of chloroacryloyl amides and alpha-methylenelactones were prepared from naltrexone and oxymorphone and some chloroacryloyl amides from fentanyl were prepared as potential Michael acceptors and irreversible ligands. The relative rates of Michael additions of p-methoxybenzenethiol to the double bonds were measured in an NMR spectrometer. The IC50's in rat brain homogenates and the irreversible binding to rat brain membranes were determined. In the methylene-lactone series, it was found that both the alpha and beta isomers derived from naltrexone and oxymorphone were excellent Michael acceptors, but only the beta isomers were more active in the opioid binding assays. The beta isomer derived from naltrexone was an irreversible ligand whereas the oxymorphone analogue was active only in the presence of 100 mM NaCl. In the chloroacryloyl series, only the alpha-chloroacryloyl amide derived from beta naltrexamine proved to be an irreversible binding ligand in the absence of NaCl. It was an excellent Michael acceptor. Under the conditions of our experiments, beta-FNA was a poor Michael acceptor and did not behave as an irreversible ligand in rat membranes.