Very high frequency proton NMR studies of the conformations of opiate agonists and antagonists

✍ Scribed by Jay A. Glasel; Herbert W. Reiher

• Publisher: John Wiley and Sons
• Year: 1985
• Tongue: English
• Weight: 696 KB
• Volume: 23
• Category: Article
• ISSN: 0749-1581
• DOI: 10.1002/mrc.1260230405

✦ Synopsis

The solution conformational properties of the opiate agonist-antagonist pairs morphinc+nalorphine and oxymorphoncwmloxone have been investigated by NMR spectroscopy of their salts and free bases in aqueous and uon-aqueous solutions, respectively. Nitrogen inversion in the piperidine ring takes place in these compounds. However, the equilibrium ratios differ between pairs. The conformations of the piperidine rings are chairs with mering degrees of distortion from ideality. On the N M R time scale the dynamically averaged orientations of the N-ally1 substituents in the antagonists difier from one another with respect to a h e d molecular coordinate system. The C-14 hydroxy group in oxymorphone-naloxone appears to be solvated, and this has important conformational effects. In these latter compounds a stereoelectronic effect takes place involving the C-6 carbonyl position (D ring), which results in differential labilization of the C-7 protons.

EXPERDlENTAL

Morphine was obtained from the State of Connecticut, Department of Consumer Affairs. Nalorphine, oxymorphone and naloxone were gifts from Merck, Sharp and Dohme and Endo Laboratories. When required, acid salts were converted into the free base forms by titration with NaOH followed by extraction or precipitation.

Sample preparation

Aqueous samples were made up in either H20 or D20 to the appropriate pH using an Ingold pH electrode and a Radiometer Model 26pH meter. All deuteriated solvents were the highest isotopic purity grades obtained from Merck, Sharp and Dohme. NMR samples were made up in Wilmad 528-PP 5 mmx 7 in tubes. Concentrations were 0.01-0.03 M.