[Food Addiction as a new behavioral addiction].

Aim of review: To overview the new studies on food addiction and highlighting the analogies and differences between food and drug addiction. RESULTS: Recent studies on food addiction have demonstrated that the neurobiological circuits involved in the development of drug addiction also play a role in food consumption, and that the uptake of nutrients by the organism is under the control of numerous complicated peripheral and central signal-transducing networks. In addition, it has also been shown that addiction and/or craving may develop toward certain foods and nutrients, too. The most recent investigations about the neurobiological systems motivating the obtaining behavior have suggested that the acquired drive toward energy rich, rewarding food contributes to the appearance of obesity as an endemic. SUMMARY: This report presents the definition of substance use disorders and describes the results of the neurobiological approaches in the study of addiction supporting the concept that food addiction is a real phenomenon. The subsequent description of the central and peripheral signaling pathways of food consumption demonstrates that while both food (nutrients) and drugs with abuse potential exert their effect on the same central neurobiological networks, the action of the peripheral signaling systems make it more difficult to understand the regulation of food intake and thus the treatment of pathological eating behavior. The presentation of the evidences of food addiction obtained in animal experiments and with imaging methods and the subsequent overview of the results achieved in the surveys of pathologic eating patterns and in the new clinical and behavioral assessment of human food addiction point to the conclusion that the pharmacological and behavioral therapy methods applied to the treatment of substance abuse disorders may also prove useful in the management of obesity.

I. Discovery of a novel series of CXCR3 antagonists. Multiparametric optimization of N,N-disubstituted benzylamines.

N,N-Disubstituted benzylamine derivatives have been identified as CXCR3 antagonists. Compounds were optimized to improve affinity and selectivity, to increase metabolic stability in human and mouse liver microsomes, to increase Caco-2 permeability. Optimization was supported by monitoring physico-chemical properties using both experimental and computational means. Several compounds with double-digit nanomolar CXCR3 affinity, favorable selectivity, microsomal stability, Caco-2 permeability and human hepatocyte clearance have been identified.

II. Discovery of a novel series of CXCR3 antagonists with a beta amino acid core.

A new series of beta amino acids, which act as CXCR3 antagonists, has been identified. The formerly optimized N,N-disubstituted benzylamine derivatives with carboxylic acid function on the N-atom was used as starting point and compounds with carboxyl function not attached to the N-atom were investigated. Affinity, metabolic stability in human and mouse liver microsomes and Caco-2 permeability were optimized. Compounds with double-digit nanomolar CXCR3 affinity, favourable microsomal stability and Caco-2 permeability have been identified.

In vitro formation of selegiline-N-oxide as a metabolite of selegiline in human, hamster, mouse, rat, guinea-pig, rabbit and dog.

It is well established in the litrature, that selegiline is metabolised to its N-dealkylated metabolites, N-desmethylselegiline, methamphetamine and amphetamine. However, most studies on selegiline metabolism did not characterize the species differences in the formation of the metabolites. Therefore, in this study, we investigated the in vitro metabolism of selegiline in liver microsomes of different species. In addition, to the previously well-characterized metabolites, selegiline-N-oxide (selegiline-NO) was found to be formed as a metabolite of selegiline in rat liver microsomal preparation. The results of experiments with liver microsomes from other species indicated species differences in the rate and extent of formation of selegiline-NO. The dog and hamster liver microsomal preparations were the most active in terms of selegiline-NO production, whereas little selegiline was metabolized to its N-oxide in human liver microsomes. When selegiline-NO was incubated with rat liver microsomes, no metabolism occurred. When a short incubation time was applied in selegiline expriments no increase in the amount of selegiline-NO was detected. Accordingly, it was clear that selegiline was not metabolized to the N-dealkylated or N,N-bis-dealkylated compounds via selegiline-NO. Studies with different isoenzyme inhibitors indicated that the formation of selegiline-NO might be catalyzed at least partly by cytochrome P450 (CYP) 2D6 and CYP3A4. With the exception of hamster microsomes in the microsomal preparations in vitro, the formation of the R,S-stereoisomer of selegiline-NO was preferred.