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)

The formation of complexes and the mode of binding to macrocyclic host molecules (alpha- and beta-cyclodextrins, 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 host-guest alignment in the complexes, but that the guest has different mobilities in the complexes formed. The MD simulations in the gas phase gave a first rough indication of the structure of each complex. The MD simulations with explicit water molecules reproduced the experimental sets of H-1-H-1 contacts and thus provided reliable information on the relative host-guest alignments and geometries of the complexes. In the beta-Cd complex the CI-844 molecule penetrates deeply into the cavity from the larger rim side with the phenyl-group moiety. An analogous relative host-guest alignment as in the beta-CD complex was found in the alpha-CD complex. In this latter case the CI-844 is not deeply embedded into the host's cavity, and the guest fluctuates widely about the equilibrium position, thus denoting lower stability of the alpha-CD-CI-844 complex with respect to the beta-CD-CI-844 complex. The use of beta-CD as host is therefore adequate for vehiculation of the drug. The relative hydrophobic-hydrophilic 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 confirmed 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 host-guest contact distances falling within 3.5 Angstrom (NOE effective) and their fluctuations. (C) 1998 John Wiley & Sons Ltd.