Molecular Determinants for Drug-Receptor Interactions. 6. Proton 500 MHz NMR Spectra of the Narcotic Antagonists Naloxone and Naltrexone by Two-Dimensional 1H–1H Chemical Shift Correlation Spectroscopy

The full analysis of the 1H NMR spectra of naloxone and naltrexone (hydrochloride salts, in 2H2O solution) was performed by using an high-frequency (500 MHz) spectrometer and the recent technique of two-dimensional (2D ) homonuclear shift spectroscopy. The 1H-1H connectivities allowed detection of correlated resonances and assignments of multiplets. The shapes of the contour levels of the COSY 45 spectra were also used to check the relative signs of coupling constants. The refinement of spectral parameters of some component spin-systems of the complex spectra was performed by computerized iterative simulation of patterns.The spectral analysis provided proton coupling constants that allowed to establish a slightly distorted-chair conformation of the piperidine ring in both compounds.The magnetic non-equivalence found for the protons bonded to C-17 atom (part of the N-alkyl fragment) was found to be larger in naltrexone than in the analogous naloxone. This fact, while no significant differences were observable in the chemical shifts of corresponding protons of the rigid molecular backbone of the two narcotic antagonists under study, was assigned to smaller degree of internal conformational flexibility of the N-methylcyclopropyl group in naltrexone with respect to that of the N-methylallyl group in naloxone.The above findings appeared in good agreement with our previously proposed views based on results from 13C relaxation times studies, which suggested the possible correlation of the motional rates of the N-methyl-R group to the pharmacological activity of antagonist compounds. This would consist in a direct correlation between decreasing flexibility of the N-bonded fragment and increasing antagonistic potency.