The study of the spectrum of pharmacological activity of the new original NT-3 mimetic dipeptide GTS-302

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Abstract

BACKGROUND: The association of the pathogenesis of neurodegenerative diseases, depression, anxiety, and cognitive disorders with the deficit of neurotrophin-3 determines the prospect of creating drugs with a similar mechanism of action. Since the use of full-size neurotrophin-3 is limited by unsatisfactory pharmacokinetic properties, it is relevant to create low-molecular-weight mimetics of neurotrophin-3 that are active when administered systemically. A dimeric dipeptide mimetic of the 4th loop of neurotrophin-3, hexamethylenediamide bis(N-γ-oxibutyryl-L-glutamyl-L-asparagine) GTS-302, which activates TrkC and TrkB receptors, has been developed at the V.V. Zakusov Research Institute of Pharmacology.

AIM: The aim of this study was to investigate the spectrum of pharmacological activity of GTS-302.

MATERIALS AND МETHODS: The pharmacological effects of GTS-302 were investigated following its intraperitoneal administration. The antidepressant-like activity of GTS-302 was studied in the forced swim test in mice after acute and 7-day administration. The anxiolytic and cognitive activity of the dipeptide were studied in the elevated plus maze test in mice and the novel object recognition test in rats after acute administration, respectively. The effect of GTS-302 on pain sensitivity was studied in the hot plate test in mice after acute administration.

RESULTS: It was found that GTS-302 exhibits antidepressant-like activity after acute administration at doses of 0.5, 1.0, 5.0 and 10 mg/kg. After 7-day administration, the antidepressant-like activity of GTS-302 was more pronounced in terms of effect size and statistical significance. The dipeptide GTS-302 at doses of 1.0, 5.0 and 10.0 mg/kg showed anxiolytic and cognitive activity and did not affect pain sensitivity.

CONCLUSIONS: The pharmacological spectrum of the low-molecular-weight mimetic of neurotrophin-3, dipeptide GTS-302, revealed upon systemic administration includes a number of neuropsychotropic effects characteristic of the full-sized neurotrophin. This allows us to consider GTS-302 as a potential neuropsychotropic drug.

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About the authors

Dmitrii M. Nikiforov

Zakusov Research Institute of Pharmacology

Email: mrdmwriter@gmail.com
ORCID iD: 0000-0002-8901-3101
SPIN-code: 7028-8335

Junior Reseаrch Associate at the Laboratory of Peptide Bioregulators of the Department of Medicinal Chemistry

Russian Federation, Moscow

Polina Y. Povarnina

Zakusov Research Institute of Pharmacology

Author for correspondence.
Email: povarnina@gmail.com
ORCID iD: 0000-0003-3278-8915
SPIN-code: 5498-6724

Cand. Sci. (Biol.), Senior Reseаrch Associate at the Laboratory of Peptide Bioregulators of the Department of Medicinal Chemistry

Russian Federation, Moscow

Tatiana A. Gudasheva

Zakusov Research Institute of Pharmacology

Email: tata-sosnovka@mail.ru
ORCID iD: 0000-0002-5185-4474
SPIN-code: 4970-0006
Scopus Author ID: 7003604408

Dr. Sci. (Biol.), Professor, Corresponding Member of the Russian Academy of Sciences, Head of the Department of Medicinal Chemistry

Russian Federation, Moscow

Anna V. Nadorova

Zakusov Research Institute of Pharmacology

Email: av-nadorova@mail.ru
ORCID iD: 0000-0002-0463-2190
ResearcherId: R-5731-2018

Reseаrch Associate at the Laboratory of Pharmacological Regulation of Addiction States

Russian Federation, Moscow

Larisa G. Kolik

Zakusov Research Institute of Pharmacology

Email: lgkolik@mail.ru
ORCID iD: 0000-0002-9847-8058
SPIN-code: 9126-6922

Dr. Sci. (Biol.), Professor of the Russian Academy of Sciences, Head of the Laboratory of Pharmacological Regulation of Addiction States

Russian Federation, Moscow

Elena A. Valdman

Zakusov Research Institute of Pharmacology

Email: evaldman@mail.ru
ORCID iD: 0000-0001-9716-499X
SPIN-code: 6806-3799

MD, Dr. Sci. (Med.), Professor, Leading Research Associate at the Laboratory of Psychopharmacology

Russian Federation, Moscow

Julia V. Vakhitova

Zakusov Research Institute of Pharmacology, , Russia

Email: juvv73@gmail.com
ORCID iD: 0000-0002-7062-8261
SPIN-code: 1391-4533

Dr. Sci. (Biol.), Corresponding Member of the Russian Academy of Sciences, Director

Russian Federation, Moscow

Sergey B. Seredenin

Zakusov Research Institute of Pharmacology

Email: seredeninpharm@mail.ru
ORCID iD: 0000-0003-4482-9331
SPIN-code: 3896-4655

MD, Dr. Sсi. (Med.), Professor, Academician of the Russian Academy of Sciences, Head of the Department of Pharmacogenetics

Russian Federation, Moscow

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2. Figure. Studying effect of dipeptide GTS-302 on locomotor activity of BALB/c mice; c. u. — conventional units. Data are presented as means and standard errors of the mean

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