N-Inversion-Associated Conformational Dynamics Is Unusually Rapid in Morphine Alkaloids

Abstract

(13)C DNMR studies of codeine and sinomenine (derivatives of N-Me morphinan) indicated that N-inversion-C-N rotation (NIR) is unusually fast for these substituted piperidines when compared with other N-Me piperidines. Since only broadening, but no signal splitting, was reached at low temperatures and the difference of chemical shifts (Delta delta) for individual conformers with the equatorially and axially oriented N-Me substituent was unavailable, the limits of the NIR barrier for these amines were determined by line shape analysis using Delta delta values provided by ab initio calculations. On the basis of the comparison of experimentally determined (13)C NMR chemical shifts for tropane conformers with the ones calculated at different theory levels for this N-Me piperidine, the B3LYP/6-31G(p)/GIAO level was chosen as a sufficiently accurate method for calculations of Delta delta. By this new "semiempirical" procedure of line shape analysis the NIR barrier for the studied morphinans lies within a 25-27 kJ mol(-1) (6.0-6.5 kcal mol(-1)) range. A low NIR barrier for morphine alkaloids is supposed to be an important factor in the activation of morphine receptor.

Conformational complexity of morphine and morphinum in the gas phase and in water. A DFT and MP2 study

“…The 13 C NMR studies show that the equatorial to axial inversion at N in morphine analogues, codeine and sinomenine, in aprotic solvents is relatively fast with an energy barrier of 25-27 kJ mol À1 . 15 A MM3 calculation of morphine yield a value of 27.6 kJ mol À1 , 16 which agree well with the experimental values. 15 Crystalline morphine exists in two polymorphic forms.…”

“…15 A MM3 calculation of morphine yield a value of 27.6 kJ mol À1 , 16 which agree well with the experimental values. 15 Crystalline morphine exists in two polymorphic forms. 17 Very recently, the X-ray structure of the stable polymorph was reported.…”

“…No similar calculations have previously been reported for morphinum, the predominating species in water solutions at physiological pH and the rst results are therefore reported herein. The energies of transition states of nitrogen inversion of morphine derivatives reported previously 15 were obtained in aprotic solvents and do not consider the various individual conformers involved in this motion. This is also the case for the MM3 calculations, which refer to the gas phase.…”

Effect of sinomenine on collagen-induced arthritis in mice

“…SIN also has been used for the treatment of opioid abstinent symptom [23]. Therefore, SIN may suppress Th1 more than Th2 via the opioid receptor since its chemical structure is similar to that of morphine [24].…”

Suppression of Th1 and Th2 Immune Responses in Mice by Sinomenine, an Alkaloid Extracted from the Chinese Medicinal Plant Sinomenium acutum

“…SIN also has been used for the treatment of opioid abstinent symptoms [23]. Therefore, SIN may more preferentially suppress Th1 than Th2 via the opioid receptor since its chemical structure is similar to that of morphine [23], [24]. Fourthly, the more marked suppression of Th1 by SIN might be in part explained by the suppression of expression of B7-DC and B7-H1 belonging to the B7 family by the alkaloid [25].…”