Naslov
The Inclusion Modes between Bupivacaine Hydrochloride and Selected Cyclodextrins Determined by ROESY Spectroscopy and Molecular Modelling Studies

Autori
Jug, Mario ; Melani, Fabrizio ; Mura, Paola

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
The 15th International Cyclodextrin Symposium: Final Program and Abstracts / Viernstein, Helmut ; Wolschann, Peter - Beč, 2010, P114-P114

Skup
15th International Cyclodextrin Symposium

Mjesto i datum
Beč, Austrija, 09.05.2010. - 12.05.2010

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
bupivacaine; cyclodextrin; ROESY; molecular modelling

Sažetak
In the present research a novel approach has been used to investigate the inclusion modes between bupivacaine hydrochloride (BVP), a sparingly soluble long acting local anaesthetic, and selected cyclodextrins. A further aim was to shed light on possible stereoselective binding between BVP and parent ß-cyclodextrin (ßCD) or anionic sulphobutylether-ß-cyclodextrin (SBEßCD). All conformations of inclusion complexes were acquired from the trajectory of molecular dynamic (MD) simulations, in agreement with the distances between selected drug and CD protons, obtained by 2D 1H-NMR spectroscopy (ROESY). MD simulations were performed by the use of the AMBER 9 software under explicit solvent (water) and periodic boundary conditions, at constant pressure and without restraints. The conformations thus collected represent the most probable conformations of the inclusion complexes formed. Since BVP molecule has a chiral centre, four possible inclusion modes have been considered. For each enantiomer, S and R, two different orientation modes into the CD cavity have been considered, i.e. one with the drug inserted from the secondary rim and another one from the primary rim of the CD cone. Molecular modelling studies of BVP complexes with SBEβCD were further complicated by the random substitution of this cyclodextrin derivative (D.S. 6.4). Therefore, two different patterns of substituent distribution have been hypothesized while building the SBEβCD structure: the first one by replacing all the primary OH groups and the second one by randomly replacing 4 primary and 3 secondary OH groups. Molecular modelling allowed determination of the most probable conformations for each complex type, by comparison of the distances calculated with those experimentally measured. The obtained results showed that complexation of BVP with ßCD preferentially occurred by inclusion of the methylated aromatic portion of the drug via the wider (secondary) rim of the cone, and that there was no chiral selectivity in the complexation process. In the case of complexes with SBEβCD, it was demonstrated that inclusion of the methylated phenyl ring of BVP via the wider rim of the cone is still the dominant binding mode, but there was an increased probability of complex formation by inclusion of the drug via the primary rim of the cone. Furthermore, the results indicated that randomly substituted SBEβCD may be considered as a more reliable model with respect to that substituted only on the primary rim. Additionally, differently from the case of βCD, there was always a significantly higher probability of inclusion complex formation with the R-enantiomer of the drug, irrespective on the substitution pattern of SBEβCD. These data may be considered as an indication of some stereoselective binding between R-BVP and SBEβCD.

Izvorni jezik
Engleski

Znanstvena područja
Farmacija

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