Aromatic amino acid-leucine dipeptides exhibit anxiolytic-like activity in young mice.

We previously reported that Tyr-Leu (YL) exhibits potent anxiolytic-like activity comparable to diazepam in mice. In the current study, we revealed that aromatic amino acid-Leu, Phe-Leu and Trp-Leu (FL and WL, respectively), exhibited anxiolytic-like activity in the elevated plus-maze and open-field tests. FL and WL were orally active. Retro-sequence peptides of FL and WL were inactive. Similarly to YL, the anxiolytic-like activities of FL and WL were inhibited by WAY100135, SCH-23390 and bicuculline, antagonists of serotonin 5-HT1A, dopamine D1 and GABAA receptors, respectively, implying that FL and WL activate a common anxiolytic pathway to that of YL. Taken together, aromatic amino acid-Leu dipeptides such as YL, FL, and WL may exhibit anxiolytic-like activity in a manner dependent on the activation of 5-HT1A, D1 and GABAA receptors.