N-Isocaproyl-L-Arginylglycine Hexamethylenediamide, First Low-Molecular-Weight Mimetic of Neurotrophin-4: Design and Neuroprotective Activity

A dimeric dipeptide mimetic of neurotrophin-4 (NT-4), N-isocaproyl-L-arginylglycine hexamethylenediamide (GZS-411), was designed based on the β-turn structure of NT-4 loop 1. GZS-411 activated the TrkB receptor similarly to the full-size neurotrophin. Neuroprotective activity of GZS-411 was observed in vitro with HT-22 mouse hippocampal cells exposed to oxidative stress or glutamate toxicity and was exerted at concentrations from 10–9 to 10–5 and from 10–8 to 10–5 М, respectively. In SH-SY5Y human neuroblastoma cells exposed to 6-hydroxydopamine toxicity, GZS-411 was active at concentrations from 10–7 to 10–5 М. The neuroprotective effect of GZS-411 was not inferior to that of the full-size protein in all models.