Dimeric Dipeptide Mimetics of Brain-Derived Neurotrophic Factor: Design and Biological Properties

BDNF may represent a beneficial therapeutically agent against a variety of neurological and psychiatric disorders, but bad pharmacokinetics complicate its clinical use. This article focuses on the design and BDNF-like biological properties of low-molecular weight dimeric dipeptide mimetics of BDNF free of these disadvantages.


Introduction
Brain-derived neurotrophic factor (BDNF) regulates the development and maintenance of the peripheral and the central nervous system predominantly through binding to the transmembrane receptor tyrosine kinase TrkB [1]. Moreover, BDNF is synthesized and released by pancreatic beta-cells and produces the insulinotropic effect [2]. Binding of BDNF with TrkB leads to the activation of various intracellular signaling pathways, including the PI3K/AKT and MAPK/ERK pathways, which are the most critical for the biological effects of BDNF [3].
BDNF is a potential therapeutic target in numerous neurological, mental and psychiatric disorders including depression [4]. However, the outcomes of several clinical trials using recombinant BDNF are disappointing [5,6] possibly because of the poor delivery and short in vivo half-life of BDNF. To address this problems, tremendous effort has been made to generate selective agonists of TrkB including peptide mimetics [7]. Bioactive BDNF exists in a form of a noncovalently linked homodimer. Each monomer contains seven beta strands connected by four hairpin loops, three of which are exposed outside (loops 1, 2, 4) and therefore may play a major role in the interaction with the receptor [8]. These compounds were constructed according to the uniform plan the central fragment of beta-turn was saved, and the preceding amino acid residue was substituted by its bioisostere, C-terminal dimerization was performed using oligomethylenediamine spacer. We studied the biological properties of GSB-214, GTS-201 and GSB-106. It was shown that all of them activate TrkB receptor and that they each have different post-receptor signaling patterns [10][11][12][13]. GSB-106 increased the levels of ERK and AKT kinase phosphorylation, whereas GSB-214 only increased the level of AKT phosphorylation and GTS-201 activated MAPK/ERK signaling cascade without affecting PI3K/AKT signaling.
The all dipeptides in concentrations of 10 -5 -10 -8 M protected HT22 neuronal cells from the H 2 O 2 -induced oxidative stress [9,10,14]. Neuroprotective activity of the active in vitro compounds was studied in vivo in a model of ischemic stroke, induced by transient middle cerebral artery occlusion (MCAO) in rats. The dimeric dipeptides GSB-106 and GSB-214 statistically significantly

Wings to the Research
An interesting observation was that GSB-106 exhibited significant antidepressant activity in the forced swimming test in mice, while GSB-214 and GTS-201 did not [9,10]. These data suggest that the both MAPK/ERK and PI3K/AKT signaling pathways are necessary for the manifestation of antidepressant activity mediated by TrkB receptors. There is literature data that describes 7,8-dihydroxyflavone (7,8-DHF), a small molecular TrkB agonist with antidepressant-like properties that provokes the PI3K/AKT and MAPK/ERK activation [16,17].
The antidepressant-like activity of GSB-106 was confirmed in a number of rodent tests [18] including forced swim test in rats and mice, tail suspension test in mice, in Nomura water wheel test in rats and in a social defeat stress model of depression in mice. Notably it is orally bioactive (0.05-5mg/kg) and is safe for chronic treatment [19,20]. GSB-106 was found to prevent stress-induced impairments of hippocampal neurogenesis [21] and stimulates hippocampal synaptogenesis [22] in mice.
Study of the antidiabetic effects (estimated from the degree of hyperglycemia and dynamics of body weight in C57Bl/6 mice with the streptozotocin -induced diabetes mellitus) of dipeptide mimetics of BDNF demonstrated [23] that GSB-214 which selectively activated PI3K/AKT possessed robust antidiabetic activity. GTS-201 selective activator of MAPK/ERK does not demonstrated any antidiabetic activity. GSB-106 activating both signaling pathways exhibited weak antidiabetic activity.
Like BDNF [24] dipeptide GSB-106 demonstrated antinoceptive effect. It significantly inhanced the pain threshold in the hot plate (by 29%) and tail flick (by 50%) tests in rats at 24h point at dose 0.1mg/kg i.e. [25]. As a result, we created dimeric dipeptide mimetics of BDNF loops 1, 2 and 4. It has been established that all these compounds activate the specific BDNF receptor TrkB and they each have different post-receptor signaling patterns. Mimetic loop 4 GSB-106 acts as a good lead compound for further development as a promising therapeutic.