Synthesis and In Vitro Neuroprotective Activity of Glycine Analogs of Gk-2 Dimeric Dipeptide Mimetic of Nerve Growth Factor 4th Loop

• Published in: Pharmaceutical chemistry journal Vol. 54; no. 2; pp. 126 - 133
• Main Authors: Sazonova, N. M., Tarasyuk, A. V., Firsova, Yu. N., Zvyagintsev, A. A., Rebeko, A. G., Antipov, P. I., Nikolaev, S. V., Antipova, T. A., Gudasheva, T. A.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-05-2020; Springer
• Subjects: Glycine; Lysine; Medicine; Nerve growth factor; Organic Chemistry; Pharmacology/Toxicology; Pharmacy; glycine scan; dipeptide; GK-2; mimetic; NGF; neuroprotective activity; structure—activity relationship
• ISSN: 0091-150X; 1573-9031
• DOI: 10.1007/s11094-020-02168-0

A dimeric dipeptide mimetic of nerve growth factor (NGF),
bis
-(
N
-monosuccinyl-L-glutamyl-L-lysine) hexamethylenediamide (GK-2), was previously developed at V. V. Zakusov State Institute of Pharmacology, activated specific TrkA receptors, and exhibited neuroprotective activity
in vitro
(10
–5
– 10
–9
M) and
in vivo
(0.1 – 10 mg/kg i.p. and p.o.). GK-2 was designed based on the beta-turn (-Asp
94
-Glu
95
-Lys
96
-Gln
97
-) of the NGF 4
th
loop and preserved the central dipeptide fragment (-Glu
95
-Lys
96
-). The Asp
94
residue was replaced by its monosuccinyl bioisostere. The dimeric structure of NGF was reproduced using a bivalent hexamethylenediamine spacer. The structure—activity (neuroprotective) relationship for GK-2 was studied in the present work using a glycine scan, i.e., successive replacement of the peptide side groups by H. The
bis
-(
N
-acetyl-L-glutamyl-L-lysine) (GK-2Ac),
bis
-(
N
-monosuccinylglycyl-L-lysine) (GK-2-Gly1), and
bis
-(
N
-monosuccinyl-L-glutamylglycine) hexamethylenediamides (GK-2-Gly2) were less active with neuroprotective activity
in vitro
under oxidative stress for HT22 cells at concentrations 10 – 100 times greater than GK-2. The conclusion was drawn that each side radical of GK-2 was important for manifestation of the full neuroprotective activity of dimeric dipeptide GK-2, a mimetic of the NGF 4
th
loop. However, removal of any of the side radicals would probably not change the active structure of the beta-turn so that the two remaining side radicals should retain the ability to bind to their TrkA subsites. This could explain the retention of neuroprotective activity in the GK-2 glycine analogs.