title: Improvement of water solubility of non-competitive AMPA receptor antagonists by complexation with beta-cyclodextrin.
abstract: The (R,S)-2-acetyl-1-(4'-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ((R,S)-1) was previously identified as a potent non-competitive AMPA receptor antagonist able to prevent epileptic seizures and reduce AMPA-induced current in electrophysiological experiments. Through the enantiomeric resolution of racemate by chiral HPLC we already demonstrated that the (R)-1 enantiomer was the eutomer. Considering the poor water solubility, these compounds have been complexed with beta-cyclodextrin (beta-CyD). The effect of beta-cyclodextrin on the spectral features of molecules was quantitatively investigated, in fully aqueous medium by phase-solubility study and the obtained diagrams suggested that it forms complexes with a molar ratio 1:1. The binding constant (K((R)-1)=15889M(-1), K((R,S)(-1))=1079 M(-1)) and the complexation efficiency (CE) were calculated. Then the solid complexes in 1:1 molar ratio were prepared by the co-precipitation method and the FTIR-ATR measurements were carried out in order to confirm the host-guest interactions that drive the complexation process, by monitoring the significant differences of the spectra of the complexes with respect to those of the corresponding physical mixtures in the same molar ratio. The experimental data have been compared with molecular modelling studies and we confirmed our hypothesis.
authors.affiliation: Dipartimento Farmaco-Chimico, Università di Messina, Viale Annunziata, 98168 Messina, Italy. rstancanelli@pharma.unime.it
authors.forename: Rosanna
authors.initials: R
authors.lastname: Stancanelli
authors.forename: Vincenza
authors.initials: V
authors.lastname: Crupi
authors.forename: Laura
authors.initials: L
authors.lastname: De Luca
authors.forename: Paola
authors.initials: P
authors.lastname: Ficarra
authors.forename: Rita
authors.initials: R
authors.lastname: Ficarra
authors.forename: Rosaria
authors.initials: R
authors.lastname: Gitto
authors.forename: Marta
authors.initials: M
authors.lastname: Guardo
authors.forename: Nunzio
authors.initials: N
authors.lastname: Iraci
authors.forename: Domenico
authors.initials: D
authors.lastname: Majolino
authors.forename: Silvana
authors.initials: S
authors.lastname: Tommasini
authors.forename: Valentina
authors.initials: V
authors.lastname: Venuti