HIGH-FIELD NMR TECHNIQUES AND MOLECULAR MODELING IN THE STUDY OF THE INCLUSION COMPLEX OF THE COGNITION ACTIVATOR SURONACRINE (HP-128) WITHCYCLODEXTRINS

The structural features of the inclusion complexes of cyclodextrins (C Ds) with the chiral cognition activator drug phenylmethyl)amino]-1,2,3 ,4-tetrahydroacridin-1-ol maleate (suronacrine maleate, HP-128) were s tudied using both high-resolution H-1 NMR spectroscopy and molecular m odelling methods. The partial inclusion of the guest from the secondar y hydroxyl side of alpha-CD was demonstrated in aqueous solution, in a ddition to a higher degree of penetration into the cavity of beta-CD f rom the same side. NMR-ROESY experiments allowed the unambiguous locat ion of the benzylic ring of the guest inside the beta-CD cavity. The f ormation of diastereoisomeric pairs was demonstrated hy the duplicatio n of the benzylic proton signals. Molecular mechanics calculations wer e used to complement the NMR analysis. Molecular modelling procedures (MacroModel interactive computer program) allowed the prediction of th e most stable structures of the complexes, and showed that specific si te interactions, provided by hydrogen bond formation, are capable of d ifferentiating the diastereoisomeric intramolecular inclusion complexe s according to available experimental NMR data.