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

Abstract

Abstract The solution conformational properties of the opiate agonist‐antagonist pairs morphine‐nalorphine and oxymorphone‐naloxone have been investigated by NMR spectroscopy of their salts and free bases in aqueous and non‐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 differing degrees of distortion from ideality. On the NMR time scale the dynamically averaged orientations of the N ‐allyl substituents in the antagonists differ from one another with respect to a fixed 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.