Peptides 62 (2014) 59–66 Contents lists available at ScienceDirect Peptides j ourna l h o mepa ge: www.elsevier.com/locate/peptides Short analogs and mimetics of human urocortin 3 display antidepressant effects in vivo Kinga Rákosi a , Tanaka Masaru b , Márta Zarándi a , Gyula Telegdy b , Gábor K. Tóth a,∗ a Department of Medical Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary b Department of Pathophysiology, Neuroscience Group of the Hungarian Academy of Sciences, University of Szeged, Semmelweis u. 1, H-6725 Szeged, Hungary a r t i c l e i n f o Article history: Received 10 July 2014 Received in revised form 29 September 2014 Accepted 29 September 2014 Available online 7 October 2014 Keywords: Depressive disorder Urocortin 3 fragments Antidepressants Peptidomimetics Azapeptides a b s t r a c t 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 under- standing 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. © 2014 Published by Elsevier Inc. Introduction Depressive disorders, some of the most prevalent psychiatric diseases, has been estimated to effect up to 21% of the world’s population [16]. Although numerous drugs are available nowadays as antidepressant agents, most of these medicines are moderately effective or ineffective in many cases. Therefore the pharmaceutical industry needs to search new type of antidepressant agents. Disturbance of the hypothalamus–pituitary–adrenal axis and corticosteroid receptor signaling are observed in conditions such as depressive, anxiogenic, and post-traumatic stress disorders [22]. It is accepted that depression, anxiety, stress and other social behavior are controlled by corticotropin-releasing hormone (CRH) [5,11,15,24]. The CRH system consists of two subtypes of CRH receptors: the CRH receptor of type 1 (CRH-1 receptors) and type 2 (CRH-2 receptors) [6,12] and four types of their ligands: CRH, uro- cortin 1 (Ucn 1), Ucn 2, and Ucn 3 [2,19]. Ucn 1 binds to both CRH-1 and CRH-2 receptors; Ucn 2 binds selectively to the CRH-2 recep- tors [23]; and Ucn 3 preferentially binds and activates the CRH-2 receptors [14]. Since the receptors and their ligands are located and distributed distinctively in the brain, the physiology and the disease ∗ Corresponding author at: Department of Medical Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary. Tel.: +36 62 545 139. E-mail address: toth.gabor@med.u-szeged.hu (G.K. Tóth). processes of the neurohumoral pathways of CRH are complicated [10]. CRH, a 41 amino acid peptide is a selective ligand of the CRH- 1 receptors and binds to the rat CRH-binding protein (rCRHBP) [21]. Physiologically, the CRH-1 receptors mediate acute stress responses, and the sustained hyperactivity of the CRH-1 receptors is considered to play a role in the pathogenesis of depressive disor- ders. A number of CRH-1 receptor antagonists proved to ameliorate depression [30]. The CRH-2 receptors appear to be stress-coping and to alleviate CRH-1 receptor stimulation [1]. The role and distri- bution of urocortin in the brain was summarized by Pan [18]. Previously, we have studied the role of the CRH receptors and their ligands Ucn 1, Ucn 2, and Ucn 3 in depression of mice in a modified forced swimming test (FST) [26]. This modified FST pre- dicts the clinical efficacy of an antidepressant drug and its effects on the adrenergic and serotoninergic nervous systems through the scoring of immobility, climbing, and swimming behavior. We demonstrated that Ucn 2 and Ucn 3 elicit antidepressant action via CRH-2 receptor stimulation [27]. Our earlier important finding was that short fragments of the native human Ucn 3 neuropeptide that consists of 38 amino acids and member of the peptide family of CRH can preserve the antidepressant-like action of the native sequence [25–28]. The smallest active fragment was found to be alanyl-glutaminyl- isoleucine-amide which is the C-terminal tripeptide of Ucn 3. The aim of the present work was the design and synthesis of novel http://dx.doi.org/10.1016/j.peptides.2014.09.023 0196-9781/© 2014 Published by Elsevier Inc.