The Impact of C-3 Side Chain Modifications on Kynurenic Acid: A Behavioral Analysis of Its Analogs in the Motor Domain

被引:16
作者
Martos, Diana [1 ]
Lorinczi, Balint [2 ,3 ]
Szatmari, Istvan [2 ,3 ]
Vecsei, Laszlo [1 ,4 ]
Tanaka, Masaru [1 ]
机构
[1] Univ Szeged, Hungarian Res Network, Danube Neurosci Res Lab, HUN REN SZTE Neurosci Res Grp, Tisza Laj Krt 113, H-6725 Szeged, Hungary
[2] Univ Szeged, Inst Pharmaceut Chem, Eotvos U 6, H-6720 Szeged, Hungary
[3] Univ Szeged, HUN REN SZTE Stereochem Res Grp, Eotvos U 6, H-6720 Szeged, Hungary
[4] Univ Szeged, Albert Szent Gyorgyi Med Sch, Dept Neurol, Semmelweis U 6, H-6725 Szeged, Hungary
关键词
tryptophan; kynurenic acid; analogs; blood-brain barrier; drug design; drug delivery; exploratory behavior; motor skills; emotions; neuropsychiatry; BLOOD-BRAIN-BARRIER; CENTRAL-NERVOUS-SYSTEM; OPEN-FIELD TEST; TRYPTOPHAN-METABOLISM; STEREOTYPED BEHAVIOR; PATHWAY METABOLITES; THERAPEUTIC TARGET; ALZHEIMERS-DISEASE; NMDA RECEPTOR; D-SERINE;
D O I
10.3390/ijms25063394
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 mu mol/4 mu L, while SZR-72 decreased vertical activity at doses of 0.04 and 0.1 mu mol/4 mu L. 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.
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页数:25
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