Synthesis and In Vitro Neuroprotector Activity of Diastereoisomers of a Dimeric Dipeptide Mimetic of Nerve Growth Factor GK-2
- Authors: Sazonova N.M.1, Tarasyuk A.V.1, Shumskii A.N.1, Rebeko A.G.1, Antipov P.I.1, Logvinov I.O.1, Antipova T.A.1, Gudasheva T.A.1
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Affiliations:
- V. V. Zakusov State Institute of Pharmacology, Russian Academy of Medical Sciences
- Issue: Vol 52, No 8 (2018)
- Pages: 704-710
- Section: Search for New Drugs
- URL: https://journals.rcsi.science/0091-150X/article/view/245421
- DOI: https://doi.org/10.1007/s11094-018-1885-3
- ID: 245421
Cite item
Abstract
Previously, a dimeric dipeptide mimetic bis-(N-monosuccinyl-L-glutamyl-L-lysine) hexamethylenediamide (GK-2) based on the β-turn of the fourth loop of nerve growth factor was prepared by us, activated TrkA, and exhibited neuroprotective activity in vitro (10–5 – 10–9 M) and in vivo (0.05 – 5 mg/kg i.p.). The present work reports the synthesis of two of its diastereomers, bis-(N-monosuccinyl-L-glutamyl-D-lysine) (GK-2LD) and bis-(N-monosuccinyl-D-glutamyl-L-lysine) hexamethylenediamides (GK-2DL). Studies of their neuroprotective activities using HT-22 neuronal culture under oxidative stress showed that switching L-lysine to D-lysine led to a significant activity decrease whereas switching L-glutamic acid to the D-stereoisomer caused it to disappear completely. Both dipeptide residues were concluded to be involved in interactions with the TrkA receptor.
Keywords
About the authors
N. M. Sazonova
V. V. Zakusov State Institute of Pharmacology, Russian Academy of Medical Sciences
Author for correspondence.
Email: saz-nelly@mail.ru
Russian Federation, 8 Baltiiskaya, Moscow, 125315
A. V. Tarasyuk
V. V. Zakusov State Institute of Pharmacology, Russian Academy of Medical Sciences
Email: saz-nelly@mail.ru
Russian Federation, 8 Baltiiskaya, Moscow, 125315
A. N. Shumskii
V. V. Zakusov State Institute of Pharmacology, Russian Academy of Medical Sciences
Email: saz-nelly@mail.ru
Russian Federation, 8 Baltiiskaya, Moscow, 125315
A. G. Rebeko
V. V. Zakusov State Institute of Pharmacology, Russian Academy of Medical Sciences
Email: saz-nelly@mail.ru
Russian Federation, 8 Baltiiskaya, Moscow, 125315
P. I. Antipov
V. V. Zakusov State Institute of Pharmacology, Russian Academy of Medical Sciences
Email: saz-nelly@mail.ru
Russian Federation, 8 Baltiiskaya, Moscow, 125315
I. O. Logvinov
V. V. Zakusov State Institute of Pharmacology, Russian Academy of Medical Sciences
Email: saz-nelly@mail.ru
Russian Federation, 8 Baltiiskaya, Moscow, 125315
T. A. Antipova
V. V. Zakusov State Institute of Pharmacology, Russian Academy of Medical Sciences
Email: saz-nelly@mail.ru
Russian Federation, 8 Baltiiskaya, Moscow, 125315
T. A. Gudasheva
V. V. Zakusov State Institute of Pharmacology, Russian Academy of Medical Sciences
Email: saz-nelly@mail.ru
Russian Federation, 8 Baltiiskaya, Moscow, 125315