Investigation of tetracaine complexation with beta-cyclodextrins and p-sulphonic acid calix[6]arenes by nOe and PGSE NMR

Abstract

Cyclodextrins (CD) and calixarenes are complexing agents that have been successfully used as pharmaceutical drug carriers, to improve the bioavailability of medicines. The aim of this work was to investigate the complexation of the local anesthetic tetracaine 1 with β-cyclodextrin 2, as well as with p-sulphonic acid calix[6]arene 3. 1H NMR experiments were carried out in D2O, i.e., with the charged tetracaine species 1. HR-DOSY 1H NMR allowed determination of the fraction of complexed population (%p bound = 55% and 70%) and the apparent association constants (K a = 1358 and 3889 M−1), respectively, for 1/2 and 1/3. These results confirm that a strong association takes place between 1 and 2, while the 1/3 complex is even more stable, due to the negatively charged sulphonic groups of 3. Studies conducted at pH 10 revealed that the association of the uncharged form of 1 with 3 is considerably weaker, while that with 2 increased significantly (K a = 6597 M−1), protecting the anesthetic against alkaline hydrolysis. 1H-ROESY 1D NMR experiments allowed determination of the host-guest relative positions, revealing that the proposed topologies for the 1/2 and 1/3 complexes were quite different. The complexation of 1 with either 2 or 3 is being investigated in view of its potential use in new therapeutic formulations, designed to increase the bioavailability and/or to decrease the systemic toxicity of tetracaine, in anesthesia procedures.