Evaluation of Anthranilamide Derivatives on Learning and Memory Processes in Naïve Rats: In Silico Predictions and In Vivo Behavioral Profiling

Background: Anthranilamides have attracted increasing attention due to their antispasmodic and anti-inflammatory effects. The present study aimed to comparatively evaluate the effects of three previously synthesized anthranilamides, namely 2-chloro-N-(2-(phenethylcarbamoyl)phenyl)benzamide (1), 2-amino-N-(3-chlorophenethyl)benzamide (2), and 2-(2-chloro-2-phenylacetamido)-N-(3,4-dimethoxyphenethyl)benzamide (3), on cognitive functions in rats and to find if those molecules could act as potential active substances for the treatment of diseases of cognitive dysfunctions. Preclinical evidence and in silico calculations suggest that these compounds may affect the acetylcholinesterase activity, which could indirectly enhance cognitive performance. Methods: Two-way active avoidance test, activity cage test, and two passive avoidance tests—step-through and step-down test—were performed. Naïve male Wistar rats were divided into 4 groups (8 rats in each group): the control group treated with DMSO and the experimental groups with the tested compounds, orally at a dose of 5 mg/kg. Results: The synthesized compounds did not impair the locomotor activity of the tested rats, with no apparent signs of motor suppression during the activity cage test. In the active avoidance test, compound (3) impaired both learning and the long-term memory test, compound (2) increased the number of conditioned stimuli responses on the 12th day as a sign of improved long-term memory, while compound (1) did not affect performance in this test. In the step-down test for passive avoidance learning it was established that compound (2) has a positive impact on the process of learning, whereas compound (1) improves learning, short-term memory, and long-term memory. Conclusions: Our results demonstrate that anthranilamide derivatives do not produce a pronounced depressant or stimulant effect on the central nervous system. Compounds (1) and (2) showed cognitive-enhancing properties, with effects varying depending on the behavioral paradigm applied. These findings highlight the potential of specific anthranilamide derivatives as modulators of learning and memory processes.