Martos, D.; Lőrinczi, B.; Szatmári, I.; Vécsei, L.; Tanaka, M. The Impact of C-3 Side Chain Modifications on Kynurenic Acid: A Behavioral Analysis of Its Analogs in the Motor Domain. Int. J. Mol. Sci.2024, 25, 3394.
Martos, D.; Lőrinczi, B.; Szatmári, I.; Vécsei, L.; Tanaka, M. The Impact of C-3 Side Chain Modifications on Kynurenic Acid: A Behavioral Analysis of Its Analogs in the Motor Domain. Int. J. Mol. Sci. 2024, 25, 3394.
Martos, D.; Lőrinczi, B.; Szatmári, I.; Vécsei, L.; Tanaka, M. The Impact of C-3 Side Chain Modifications on Kynurenic Acid: A Behavioral Analysis of Its Analogs in the Motor Domain. Int. J. Mol. Sci.2024, 25, 3394.
Martos, D.; Lőrinczi, B.; Szatmári, I.; Vécsei, L.; Tanaka, M. The Impact of C-3 Side Chain Modifications on Kynurenic Acid: A Behavioral Analysis of Its Analogs in the Motor Domain. Int. J. Mol. Sci. 2024, 25, 3394.
Abstract
The central nervous system (CNS) is the final frontier in drug delivery because of the blood-brain barrier (BBB), which poses significant barriers to the access of most drugs to their targets. Kynurenic acid (KYNA), a tryptophan (Trp) metabolite, plays an important role in behavioral functions and abnormal KYNA levels have been observed in neuropsychiatric conditions. The current challenge lies in delivering KYNA to the CNS owing to its polar side chain. Recently, C-3 side chain modified KYNA analogs have been shown to cross the BBB; however, it is unclear whether they retain the biological functions of the parent molecule. This study examined the impact of KYNA analogs, specifically SZR-72, SZR-104, and the newly developed SZRG-21, on behavior. The analogs were administered intracerebroventricularly (i.c.v.), and their effects on the motor domain were compared with those of KYNA. Specifically, open field (OF) and rotarod (RR) tests were employed to assess motor activity and skills. SZR-104 increased horizontal exploratory activity in the OF test at a dose of 0.04 μmol/4 μL, while SZR-72 decreased vertical activity at doses of 0.04 and 0.1 μmol/4 μL. In the RR test, however, neither KYNA nor its analogs showed any significant differences in motor skills at either dose. Side chain modification affects affective motor performance and exploratory behavior, as the results show for the first time. In this study, we showed that KYNA analogs alter emotional components such as motor-associated curiosity and emotions. Consequently, drug design necessitates the development of precise strategies to traverse the BBB while paying close attention to modifications in their effects on behavior.
Keywords
tryptophan; kynurenic acid; analogs; blood-brain barrier; drug design; drug delivery; exploratory behavior; motor skills, emotions; neuropsychiatry
Subject
Medicine and Pharmacology, Medicine and Pharmacology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
