Molecular determinants for drug–receptor interactions. Part 7. 500 MHz 1H nuclear magnetic resonance spectra of the narcotic agonists morphine and oxymorphone and of the morphine-related antagonist nalorphine by two-dimensional 1H–1H chemical shift correlation spectroscopy

Abstract

The high frequency (500 MHz)¹H n.m.r. spectra of the narcotic agonists morphine and oxymorphone and of the mixed agonist–antagonist nalorphine (hydrochloride salts) were run in ²H₂O and fully analysed in terms of chemical shifts and coupling constants. Detection of correlated resonances, relative signs of coupling constants and assignments of multiplets were made possible by two-dimensional (2D) homonuclear shift spectroscopy. The coupling constant determined provided evidence that the piperidine ring adopts a slightly distorted-chair conformation in all these compounds. Selective broadening of the signals of the protons in the 10, 15, 16, and 17 positions was observed in the morphine and nalorphine spectra at 296 K. This was consistent with an inversion process occurring between the two configurational isomers with axial and equatorial N-alkyl group. Resolved patterns were attained at 345 and 330 K for morphine and nalorphine, respectively. This demonstrated that the increase of temperature was sufficient to make the inversion process rates fast on the n.m.r. time-scale. All portions of the spectrum of oxymorphone were sharp at 296 K, showing that a single diastereoisomer (equatorial N-alkyl group) is present for this molecule. A possible correlation was proposed between restricted conformational freedom along the chain of the N-alkyl group and the relative narcotic antagonist potency of nalorphine, naloxone, and naltrexone.