Title:Synthesis and Biological Analysis of Anti-addiction Effect and Hepatotoxicity of Tow Baclofen Analogues Complexed with β-Cyclodextrin
Volume: 25
Issue: 1
Author(s): Assia Keniche*, Ibtissem EL Ouar, Ibtissem Zeghina and Mohammed El Amine Dib
Affiliation:
- Laboratoire de Chimie Organique, Substances Naturelles et Analyses (COSNA), Universite de Tlemcen, BP 119, 13000,Algeria
Keywords:
Baclofen, cyclodextrin, inclusion complex, analogues, anti-addiction, hepatotoxicity activities.
Abstract:
Aim and Objective: The excessive consumption of alcohol and the installation of
dependence is, in most cases, facilitated by favorable psychological factors that trigger and
maintain the behavior of consumers. Examples more frequently encountered in individuals having
difficulty with alcohol are, in particular: one or more anxiety disorders, deficits in the capacities to
manage stress and anxiety. The main objective of this work was to study in vivo the anti-addiction
effect and hepatotoxicity of tow baclofen analogues complexed with β-Cyclodextrin (βCD) on an
alcohol-dependent rat model.
Materials and Methods: The synthesis of two analogues, ABF1 and ABF2, close to baclofen was
reported. The structural determination of the two compounds was confirmed by NMR and IR
analysis. The complexation of analogues with β-Cyclodextrin (βCD) was performed in water at
room temperature (25 °C). The interactions of ABF with β-Cyclodextrin, and the stability constant
(Ka) of the inclusion complex formed between them were investigated by using UV-visible
spectroscopy. The biological effects of baclofen and the two analogues on alcohol dependence
were studied in wistar rats. The anti-addiction effect of the analogues was tested by measuring the
alcohol intake and the variation of the animal behaviour. The toxicity of the compounds was also
analysed on liver injury markers.
Results: The amino-3-phenylbutanoic acid (ABF1) and 3,4,5-trihydroxy-N-(methyl-2-acetate)
benzamide (ABF2) were synthesized. The complexation of both analogues of baclofen (BF) with
β-cyclodextrin (βCD) (ABF- βCD) was realized and confirmed by the stability constant of the
inclusion complex (Ka) and Job’s method. The evaluation of anti-addiction activity in vivo showed
that ABF1-βCD inhibits the consumption of alcohol at doses equivalent to those of baclofen. Both
baclofen analogues have shown an anxiolytic effect. Regarding the toxicity of the two compounds,
our results showed that ABF1-βCD has less toxic effect than baclofen; it reduces the activity of
ALT and AST enzymes. Histologically, ABF1-βCD has no effect on the liver structure and has a
protective effect against lesions alcohol-induced liver disease.
Conclusion: Therefore, it can be suggested that ABF1 analogue combined with β-Cyclodextrin can
be used as a treatment for alcohol dependence. Further clinical works are needed to confirm its
effectiveness.
