Study of the Pharmacological Activity Spectrum of the New Original NT-3 Mimetic Dipeptide GTS-302

Abstract

The association of the pathogenesis of neurodegenerative diseases, depression, anxiety, and cognitive disorders with neurotrophin-3 deficiency determines the prospect of creating drugs with a similar mechanism of action. Since the use of full-length NT-3 is limited by unsatisfactory pharmacokinetic properties, the creation of low-molecular mimetics of neurotrophin-3 that are active when administered systemically is relevant. The Federal Research Center for Innovator and Emerging Biomedical and Pharmaceutical Technologies has created a dimeric dipeptide mimetic of the 4th loop of NT-3, hexamethylenediamide bis-(N-γ-oxybutyryl-L-glutamyl-L-asparagine) with the laboratory code GTS-302, which activates TrkC and TrkB receptors. Purpose. The purpose of the work was to study the range of pharmacological activity of GTS-302. Materials and methods. The pharmacological effects of GTS-302 were revealed by its intraperitoneal administration. The antidepressant-like activity of GTS-302 was studied in the forced swimming test on mice after its acute and 7-day administration. The anxiolytic and memory-enhancing activities of the dipeptide were studied, respectively, in the elevated plus maze on mice and in the novel object recognition test on rats after acute administration. The effect of GTS-302 on pain sensitivity was studied in the hot plate test on mice after acute administration. Results. It was found that GTS-302 exhibits antidepressant-like activity upon acute administration at doses of 0.5, 1.0, 5.0, and 10 mg/kg. At 7-day administration, the antidepressant-like activity of GTS-302 was more pronounced in terms of the effect expression and statistical significance. Dipeptide GTS-302 at doses of 1.0, 5.0, and 10.0 mg/kg exhibited anxiolytic and memory-enhancing activity and did not affect pain sensitivity. Conclusions. The pharmacological spectrum of the low-molecular NT-3 mimetic dipeptide GTS-302, revealed during systemic administration, includes a number of neuropsychotropic effects characteristic of a full-size neurotrophin. This allows GTS-302 to be considered as a potential neuropsychotropic drug.