Comparative host–guest complex formation of the Alzheimer’s drug memantine with para-sulfonatocalix[n]arenes (n = 4 or 8)

Abstract

The comparative encapsulation of the Alzheimer’s drug memantine (3,5-dimethyladamantan-1-amine), used as its hydrochloride salt, within the cavity of two different sized para-sulfonatocalix[n]arenes (sCX[n]; n = 4 or 8) was analysed by ¹H NMR spectroscopy. Addition of either macrocycle to memantine results in selective upfield shifts of all drug proton resonances of between 0.50 and 1.72 ppm for sCX[4] and between 0.80 and 1.53 ppm for sCX[8]. Memantine binding results in the observation of an extra sCX[4] resonance for the macrocycle’s methylene protons, which is not observed for the larger sCX[8], indicating a potential change in shape of the sCX[4] upon host–guest formation. Difference in changes to the chemical shift of the memantine doublet-of-doublets resonance for both macrocycles indicates a potential change in shape of memantine upon host–guest formation. From Job Plots, memantine binds to sCX[4] in a 1:1 ratio with a binding constant of 6.6 × 10⁶ M⁻¹, whereas binding to sCX[8] is in a 1:2 host–guest ratio. Overall, the results indicate that memantine forms subtly different host–guest complexes with different sized sCX[n] homologues, which could be used to tune the drug delivery potential of the macrocycle for different pharmaceutical applications.