Glyproline Pro-Ampakine with Neuroprotective Activity

Previously it was shown that neuropeptide cyclo-L-prolylglycine (CPG) is a positive modulator of AMPA receptors, which increases BDNF level in neuronal cell cultures. The spectrum of CPG’s pharmacological effects corresponds to that of BDNF. Dipeptide N-phenylacetyl-glycyl-L-proline ethyl ester (GZK-111) was designed and synthesized as a linear analog of CPG. The aim of the present work was to reveal the pharmacological profile of GZK-111. Dipeptide GZK-111 was shown to metabolize into CPG in vitro and increased cell survival by 28% at concentrations of 10-7–10-6 M in a Parkinson’s disease cell model. In a model of cerebral ischemia, GZK-111, at a dose of 0.5 mg/kg, i.p., was found to have neuroprotective effects, reducing the cerebral infarct volume by 1.6 times. Similar to CPG, GZK-111, at the range 0.1–1.0 mg/kg, i.p., possessed a stereospecific antiamnesic activity. A significant anxiolytic effect was observed at a dose of 1.5 mg/kg. GZK-111, at the range 0.5–4.0 mg/kg, i.p., demonstrated analgesic activity. GZK-111, at a dose of 10 mg/kg/7 days, i.p., possessed antidepressant-like activity. So, the neuroprotective, nootropic, antihypoxic, anxiolytic, antidepressant-like, and analgesic effects of GZK-111 were revealed. Thus, GZK-111 can be considered as a pharmacologically active pro-ampakine with a BDNF-ergic mechanism of action.