Molecular determinants for drug-receptor interactions. 8. Anisotropic and internal motions in morphine, nalorphine, oxymorphone, naloxone and naltrexone in aqueous solution by carbon-13 NMR spin-lattice relaxation times |
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Authors: | Antonio Grassi Bruno Perly Giuseppe C. Pappalardo |
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Affiliation: | a Dipartimento di Scienze Chimiche, II Cattedra di Chimica Generale, Facoltà di Farmacia, Università di Catania, Viale A. Doria 6, 95125 Catania, Italy b CEN Saclay, DPC/SCM, 91191 Gif-sur-Yvette, France |
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Abstract: | Carbon-13 NMR spin-lattice relaxation times (T1) were measured for morphine, oxymorphone, nalorphine, naloxone and naltrexone as hydrochloride salts in 2H2O solution. The data refer to the molecules in the N-equatorial configuration. The experimental T1 values were interpreted using a model of anisotropic reorientation of a rigid body with superimposed internal motions of the flexible N-methyl, N-methyl-allyl and N-methyl-cyclopropyl fragments. The calculated internal motional rates were found to markedly decrease on passing from agonists to mixed (nalorphine) and pure (naloxone, naltrexone) antagonists. For these latter the observed trend of the internal flexibility about N---C and C---C bonds of the N-substituents is discussed in terms of a correlation with their relative antagonistic potencies. In fact, such an evidence of decreasing internal conformational dynamics in the order nalorphine, naloxone, naltrexone, appeared interestingly in line with the “two-state” model of opiate receptor operation mode proposed by Snyder. |
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