Molecular determinants for drug–receptor interactions. Part 5. Anisotropic and internal motions in analgesic narcotics (morphine, oxymorphone) and related antagonists (nalorphine, naloxone) by carbon-13 nuclear magnetic resonance spin–lattice relaxation times

Abstract

Carbon-13 n.m.r. spin–lattice relaxation times (T₁) were measured for two pairs of related agonist–antagonist narcotic analgesics, morphine–nalorphine and oxymorphone–naloxone, in (CD₃)₂SO–CDCl₃ solution. The experimental T₁ values were interpreted using a model of anisotropic reorientation of a rigid body. Fitting procedures provided the parameters of the overall molecular motion (diffusion coefficients and Eulerian angles) for each compound. Additional calculations were made by assuming a model of anisotropic reorientation of a rigid body with overimposed internal motions of the flexible N-methyl and N-allyl groups. This model was adequate to reproduce also the relaxation times of the carbon atoms undergoing internal free rotation. The motional parameters indicate a smaller rotational diffusion rate for the N-allyl fragment of naloxone as well as for the whole molecule with respect to the other compounds. The N-methyl group of the morphine molecule rotates at a greater rate than the same group in oxymorphone or the N-allyl moieties in the remaining molecules.