NMR spectroscopic evidence and molecular dynamics studies on inclusion and non-inclusion phenomena between β-cyclodextrin and new anti-Alzheimer's drugs tacrine (CI-970), velnacrine (HP-029) and suronacrine (HP-128)

Abstract

The formation of supramolecular complexes of β-CD with new generation anti-Alzheimer's agents of the 1,2,3,4-tetrahydro-9-aminoacridine family (tacrine hydrochloride, 1, velnacrine maleate, 2 and suronacrine maleate, 3), has been studied using molecular dynamics (MD) simulations both in vacuo and with a water sphere. High-field NMR experiments for 1 and 2 gave experimental evidence of their effective non-inclusion. However, earlier NMR studies demonstrated inclusion of 3 on the basis of the observed upfield shifts of the 3-H and 5-H protons of the β-CD cavity.

MD calculations performed for molecules in vacuo gave uncertain results that evidenced failure of this model to reproduce consistently the set of the three experiments. Such a failure was overcome by including explicitly water molecules in the model, thus showing that an oversimplified model for modelling complexes of charged molecules is susceptible to incorrect conclusions.

The calculations performed for cations 1, 2 and 3 in the water sphere also showed that 1 and 2 are more hydrophilic than 3. This suggests that the relative strength of the solvation and of the complex formation constants favours complexation of 3 instead of its non-inclusion, and vice versa in the cases of 1 and 2.

An important general aspect of β-CD supramolecular complexes of charged species was found to be controlled by the solvation effects that must be necessarily included to correctly model, in the absence of safe experimental information like that coming from NMR, inclusion or non-inclusion of a guest into the host.