Study of antidepressant activity of pyroglutamic acid derivatives in a model of reserpine depression in mice

Depression is a common and significant mental disorder. Previously, among the C(4)-derivatives of pyroglutamic acid synthesized by us, low-toxic compounds with psychotropic activity in vivo were identified. The purpose of the work: To screen new pyroglutamic acid derivatives for antidepressant activity and to study the effect of potential antidepressants in a reserpine-induced depression model. Materials and methods: The study was performed on adult male white mice weighing 25–35 g. The 17 test compounds, reference drugs (fluoxetine and amitriptyline), or a vehicle solution were administered intragastrically to mice of the corresponding groups 1 hour before the experimental sessions. For screening in the tail suspension test (TST), the test compounds were administered at a dose of 1/10 Mr/kg; then, effective doses for the active compounds were determined. To model depression, reserpine was administered to mice intraperitoneally at a dose of 1 mg/kg 20 h before, and the compounds selected in the screening and amitriptyline were administered 1 h before the beginning of the experimental session with the TST, Porsolt forced swimming test and sucrose anhedonia test. Results and discussion: A decrease in immobility in the TST screening was observed under the action of fluoxetine and compounds VAY1376, VAY1392, IAN1512, which it was decided to study further at a dose of 1/10 Mr/kg. In the depression model, reserpinized animals, compared with intact ones, showed less preference for sucrose and activity in the TST and forced swimming test. Compounds VAY1392 and IAN1512, comparable to amitriptyline, reduced the severity of all these manifestations of depression; VAY1376 was able to alleviate only the decrease in sucrose preference and active swimming time, but not immobilization. Conclusion: In a screening of antidepressant activity by the TST, compounds VAY1376, IAN1512, and VAY1392 were selected from 17 pyroglutamic acid derivatives at an effective dose of 1/10 Mr/kg. In a model of reserpine-induced depression, IAN1512 and VAY1392 neutralized depressive-like behavior comparable to amitriptyline; however, VAY1376 showed conflicting results, which may indicate heterogeneity or a different mechanism of action.