Synthesis and In Vitro Neuroprotector Activity of Diastereoisomers of a Dimeric Dipeptide Mimetic of Nerve Growth Factor GK-2

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.