Short analogs and mimetics of human urocortin 3 display antidepressant effects in vivo

•Depressive disorders are one of the most prevalent psychiatric diseases.•Most of the medicines available nowadays are moderately effective or ineffective.•We found previously that urocortin 3 peptide displays antidepressant activity.•The shortest active fragment was the C-terminal tripeptide of urocortin 3 (Ucn 3).•Novel short analogs of Ucn 3 were synthesized preserving the antidepressant effect.

Peptide analogs of urocortin 3[36–38] (Ucn 3[36–38]), obtained with deletion or replacement of amino acids of the original human urocortin 3 sequence, were designed, synthesized, and tested in vivo for treatment of depression. Based on the results of the biological tests of the peptide analogs, several new peptidomimetics of the above short analogs of urocortin 3, including urea- and azapeptides, were also designed and synthesized and found to preserve the antidepressant-like effect of the 38 amino acid long original neuropeptide. The molecular modifications of urocortin 3[36–38] led to an improved understanding of the relationship between molecular structure and biological activity of this peptide, and the novel peptidomimetics could be further tested for possible clinical treatment of depression.