Theoretical and experimental study of the tetracain/β-cyclodextrin inclusion complex

Abstract

The local anaesthetic Tetracain has previously been found to block, induce or potentiate Ca2+ release from the sarcoplasmic reticulum of skeletal muscle. Cyclodextrins (CD) are complexing agents that have been successfully used as pharmaceutical drug carriers, to improve the bioavailability of medicines. The aim of this work is to investigate the inclusion process of the local anesthetic Tetracain with the beta-cyclodextrin at the Hartree–Fock level of theory calculations with a 6-31G (d) basis set, and to evaluate stabilization upon the formation of the inclusion compounds for 1:1 association. The inclusion process pathways are described and the most stable structures of the different complexes are sought through a global potential energy scan. The data suggest that the most stable structure for the 1:1 stoichiometry between the Tetracain and the β-CD is obtained when the inclusion complex formed by Tetracain from the tertiary amine group, entering into the cavity of β-CD from its narrow side (i.e. the primary 6-CH2OH hydroxyl group). Structure–activity relationship is discussed in terms of different molecular descriptors and experimental Raman spectroscopy measurements at different mole fraction for the inclusion complexes analyzed and compared with our theoretical constructed Raman spectra.