HIGH-FIELD NMR SPECTROSCOPIC TECHNIQUES COMBINED WITH MOLECULAR-DYNAMICS SIMULATIONS FOR THE STUDY OF THE INCLUSION COMPLEXES OF ALPHA-CYCLODEXTRIN AND BETA-CYCLODEXTRIN WITH THE COGNITION ACTIVATOR 3-PHENOXYPYRIDINE SULFATE (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 s tudied using NMR techniques (T-ROESY) complemented by molecular dynami cs (MD) protocols which allowed complete interpretation of the NMR exp erimental data. The NMR experiments indicated that a 1:1 stoichiometry of the complexes exists and revealed dipolar contacts between selecte d protons of the guest and inner protons of the hosts. The NMR data su ggest the same relative host-guest alignment in the complexes, but tha t the guest has different mobilities in the complexes formed. The MD s imulations in the gas phase gave a first rough indication of the struc ture of each complex. The MD simulations with explicit water molecules reproduced the experimental sets of H-1-H-1 contacts and thus provide d reliable information on the relative host-guest alignments and geome tries of the complexes. In the beta-Cd complex the CI-844 molecule pen etrates deeply into the cavity from the larger rim side with the pheny l-group moiety. An analogous relative host-guest alignment as in the b eta-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 gues t fluctuates widely about the equilibrium position, thus denoting lowe r 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 energet ics of the phenyl and pyridinium rings of CI-844 were the factor deter mining the orientation of the guest in the inclusion process. The stud y also confirmed the importance of including explicitly the solvent mo lecules in the simulations of ionic systems in order to interpret corr ectly the experimental data and the location of the host-guest contact distances falling within 3.5 Angstrom (NOE effective) and their fluct uations. (C) 1998 John Wiley & Sons Ltd.