High-field NMR spectroscopic techniques combined with molecular dynamics simulations for the study of the inclusion complexes of α- and β-cyclodextrins with the cognition activator 3-phenoxypyridine sulphate (CI-844)
✍ Scribed by Maria E. Amato; Kenny B. Lipkowitz; Giuseppe M. Lombardo; Giuseppe C. Pappalardo
- Publisher
- John Wiley and Sons
- Year
- 1998
- Tongue
- English
- Weight
- 311 KB
- Volume
- 36
- Category
- Article
- ISSN
- 0749-1581
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✦ Synopsis
The formation of complexes and the mode of binding to macrocyclic host molecules (a-and bcyclodextrins, CDs) of the nootropic drug CI-844 (3-phenoxypyridine sulphate, Warner-Lambert/Parke-Davis) were studied using NMR techniques (T-ROESY) complemented by molecular dynamics (MD) protocols which allowed complete interpretation of the NMR experimental data. The NMR experiments indicated that a 1 :1 stoichiometry of the complexes exists and revealed dipolar contacts between selected protons of the guest and inner protons of the hosts. The NMR data suggest the same relative hostÈguest alignment in the complexes, but that the guest has di †erent mobilities in the complexes formed. The MD simulations in the gas phase gave a Ðrst rough indication of the structure of each complex. The MD simulations with explicit water molecules reproduced the experimental sets of 1HÈ1H contacts and thus provided reliable information on the relative hostÈguest alignments and geometries of the complexes. In the b-Cd complex the CI-844 molecule penetrates deeply into the cavity from the larger rim side with the phenyl-group moiety. An analogous relative hostÈguest alignment as in the b-CD complex was found in the a-CD complex. In this latter case the CI-844 is not deeply embedded into the hostÏs cavity, and the guest Ñuctuates widely about the equilibrium position, thus denoting lower stability of the a-CDÈ CI-844 complex with respect to the b-CDÈCI-844 complex. The use of b-CD as host is therefore adequate for vehiculation of the drug. The relative hydrophobicÈhydrophilic energetics of the phenyl and pyridinium rings of CI-844 were the factor determining the orientation of the guest in the inclusion process. The study also conÐrmed the importance of including explicitly the solvent molecules in the simulations of ionic systems in order to interpret correctly the experimental data and the location of the hostÈguest contact distances falling within 3.5 (NOE Ó e †ective) and their Ñuctuations.