%0 Journal Article %A LEIF J. SAETHRE %A THOMAS A. CARLSON %A JOYCE J. KAUFMAN %A WALTER S. KOSKI %T Nitrogen Electron Densities in Narcotics and Narcotic Antagonists by X-ray Photoelectron Spectroscopy and Comparison with Quantum Chemical Calculations %D 1975 %J Molecular Pharmacology %P 492-500 %V 11 %N 4 %X Nitrogen 1s electron binding energies of narcotics and, where possible, of their congener narcotic antagonists have been measured by X-ray photoelectron spectroscopy (ESCA) (binding energies of the inner 1s shell electrons on an atom are known to be directly related to the valence shell electron densities on these atoms). The compounds investigated include the narcotic-(N-methyl)-narcotic antagonist (the N-allyl derivative of the narcotic) pairs morphine-nalorphine, oxymorphone-naloxone, and levorphanol-levallorphan, as well as methadone and cyclazocine. The ESCA spectra show that to within 0.2 eV (or 0.01 electron charge unit) the electron densities (either total or valence) on the nitrogen atoms in congener agonist-antagonist pairs are identical. These results confirm most convincingly our earlier quantum chemical CNDO/2 (complete neglect of differential overlap) results, which showed most surprisingly, contrary to customary pharmacological assumptions, that these electron densities are the same. These results also indicate that measured solution pKa values cannot be directly correlated with nitrogen electron densities. For several of these compounds the ESCA spectra were determined for both the free bases and the acid salts. These results also confirm the predictions from the earlier CNDO/2 calculations that for the protonated species the entire positive charge is not localized on the nitrogen atom. Only about 0.2 positive charge (or a little less) residues on the nitrogen, the remainder being delocalized over the neighboring atoms. This has significant implications for the requisites that the complementary "analgesic" or "opiate" receptor must possess, which are somewhat different from those heretofore postulated by pharmacologists. ACKNOWLEDGMENTS We thank the following for their gracious gifts of some of the compounds used in this research: naloxone and oxymorphone, Dr. H. Blumberg, Endo Laboratories, Inc.; nalorphine, Dr. F. Robinson, Merck Sharp & Dohme; levorphanol and levallorphan, Dr. W. E. Scott, Hoffmann-La Roche, Inc.; cyclazocine, Dr. F. Nachod, Sterling-Winthrop Research Institute; and methadone, Dr. E. May, National Institutes of Health. %U https://molpharm.aspetjournals.org/content/molpharm/11/4/492.full.pdf